WO2007148135A1 - Macrocyclic compounds as antiviral agents - Google Patents

Abstract

The present invention relates to macrocyclic compounds of formula (I): wherein W, n, m, R1, R2, R3, R4, R5, Ra, M, Z and ring B are defined herein, and pharmaceutically acceptable salts thereof, pharmaceutical co mposit ions comprising them, and their use for the treatment or prevention of infection by hepatitis C virus.

Description

Macrocyclic compounds as antiviral agents

The present invention relates to macrocyclic compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infection.

Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. According to the World Health Organization, there are more than 170 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their offspring. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection. Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA- dependent RNA polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein, and is considered a prime drug target since it is responsible for an intramolecular cleavage at the NS3/4A site and for downstream intermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B junctions. Previous research has identified classes of peptides, such as hexapeptides as well as tripeptides discussed in U.S. patent applications US2005/0020503, US2004/0229818, and US2004/00229776, showing degrees of activity in inhibiting the NS3 protease. The aim of the present invention is to provide further compounds which exhibit activity against the HCV NS3 protease.

Macrocyclic compounds that exhibit activity against the HCV NS3 protease have already been disclosed in published International patent application nos. WO2006/119061, WO2007/015855 and WO2007/016441 (all Merck & Co., Inc.)

Thus, in one aspect, there is provided the compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3 or 4; n is 0, 1 or 2;

R¹ is CO₂R⁶, CONR⁶SO₂ R⁶ or CONR⁶SO₂N(R⁶),;

R² is H, Ci-₆alkyl, C₂-₆alkenyl or Q-scycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;

R³ is Ci-₆alkyl, (CH₂)₀-₃C₃-₈cycloalkyl, (CH₂)₀-₃aryl or (CH₂)₀-₃Het, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃, NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂;

R⁴ is hydrogen, halo, hydroxy, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, (CH₂)₀-₃C₃_₈cycloalkyl, (CH₂)₀-₃aryl or Ci_₆alkoxy, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃ NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂; R⁵ is hydrogen, halo, hydroxy, Ci-₆alkyl, Ci-₆alkoxy, CN, NO₂, C₃_₈cycloalkyl, N(R⁶)₂, aryl or heteroaryl, optionally substituted by 1 to 8 halo, Ci^alkyl or N(R⁶)₂; each R⁶ is independently hydrogen, Ci-₆alkyl or C₃_₈cycloalkyl; R^a is hydrogen or Ci^alkyl; or R^a and R³ are joined to form a 5- to 7-membered heterocycle containing 1, 2 or 3 N atoms, which heterocycle is optionally substituted by Ci^alkyl; each W is independently halo, OR⁶, d_₆alkyl, CN, NO₂, CF₃, OCF₃, OCHF₂, CO₂R⁶, CON(R⁶)₂, COR⁶, NR⁶C(O)R⁶, aryl or heteroaryl; Z is a bond, -CH₂- or C=O;

M is C₂_i₂alkylene or C₂_i₂alkenylene, optionally substituted by halo, Ci_6alkyl, (CH₂)o-₃C₃_₈cycloalkyl or (CH₂)₀-₃aryl, and optionally containing O, NR⁶, S, SO or SO₂; and

ring B is

and ring A is pyridinyl, pyrrolidinyl or pyrimidinyl.

In one embodiment of the present invention, there is provided the compound of formula (Io):

or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3 or 4; n is 0, 1 or 2;

R¹ is CO₂R⁶, CONR⁶SO₂ R⁶ or CONR⁶SO₂N(R⁶),; R² is H, Ci-₆alkyl, C₂-₆alkenyl or d-scycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;

R³ is Ci-₆alkyl, (CH^o^d-scycloalkyl, (CH₂)₀-₃aryl or (CH₂)₀-₃Het, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃, NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂; R⁴ is hydrogen, C^aUcyl, C₂_₆alkenyl, C₂_₆alkynyl, (CH₂)₀-₃C₃_₈cycloalkyl, (CH₂)₀-₃aryl or d_₆alkoxy, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃ NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂;

R⁵ is hydrogen, halo, hydroxy, Ci-₆alkyl, Ci-₆alkoxy, CN, NO₂, C₃_₈cycloalkyl, N(R⁶)₂, aryl or heteroaryl, optionally substituted by 1 to 8 halo, Ci^alkyl or N(R⁶)₂; each R⁶ is independently hydrogen, Ci-₆alkyl or C₃_₈cycloalkyl;

R^a is hydrogen or Ci^alkyl; or R^a and R³ are joined to form a 5- to 7-membered heterocycle containing 1, 2 or 3 N atoms, which heterocycle is optionally substituted by Ci^alkyl; each W is independently halo, OR⁶, d_₆alkyl, CN, NO₂, CF₃, OCF₃, OCHF₂, CO₂R⁶, CON(R⁶)₂, COR⁶, NR⁶C(O)R⁶, aryl or heteroaryl; Z is a bond or C=O;

M is C₂_i₂alkylene or C₂_i₂alkenylene, optionally substituted by halo, C^aUcyl, (CH₂)o-₃C₃_₈cycloalkyl or (CH₂)₀-₃aryl, and optionally containing O, NR⁶, S, SO or SO₂; and ring A is pyridinyl, pyrrolidinyl or pyrimidinyl.

In another embodiment of the present invention, m is 1 or 2. Preferably, m is 1.

In another embodiment of the present invention, n is 0 or 1. Preferably, n is 0.

In another embodiment, R¹ is CO₂R⁶, CONR⁶SO²R⁶ or CONR⁶SO₂N(R⁶)₂ where R⁶ is as hereinbefore defined. Preferably, R¹ is CO₂R⁶ or CONR⁶SO₂R⁶ where R⁶ is as hereinbefore defined. More preferably, R¹ is CO₂H or CONHSO₂R⁶ where R⁶ is as hereinbefore defined. Especially, R¹ is CO₂H or CONHSO₂-C₃_₈cycloalkyl. More especially, R¹ is CO₂H or CONHSO₂-C₃_₆cycloalkyl. Most especially, R¹ is CO₂H or CONHSO₂-cyclopropyl.

In another embodiment, R² is C^aUcyl or C₂_₆alkenyl. Preferably, R² is Ci^alkyl or C₂. ₄alkenyl. More preferably, R² is Ci_₂alkyl or -CH=CH₂. Most preferably, R² is ethyl or - CH=CH₂.

In another embodiment, R³ is Ci_₆alkyl, or (CH₂)₀-₃C₃_₈cycloalkyl, optionally substituted by halo, OR⁶ or C^aUcyl, where R⁶ is as hereinbefore defined. Preferably, R³ is C^aUcyl or (CH₂)o-3C3_8cycloalkyl, optionally substituted by halo. More preferably, R³ is Ci^alkyl or C₃. ₆cycloalkyl, optionally substituted by fiuoro or chloro. Most preferably, R³ is methyl, propyl, butyl, cyclopentyl or cyclohexyl, optionally substituted by fiuoro. Especially, R³ is methyl, 'propyl, 'butyl, CF₃, cyclopentyl or cyclohexyl.

In another embodiment, R^a is hydrogen or Ci_₂alkyl. Preferably, R^a is hydrogen or methyl.

In another embodiment, R^a and R³ are joined to form a 5- or 6- membered heterocycle containing 1 or 2 N atoms, which heterocycle is optionally substituted by Ci^alkyl. Preferably, R^a and R³ are joined to form a 5- or 6- membered heterocycle containing one N atom, which heterocycle is optionally substituted by Ci^alkyl. More preferably, R^a and R³ are joined to form a pyrrolidinyl or a piperidinyl ring, optionally substituted by Ci_₂alkyl. Most preferably, R^a and R³ are joined to form a pyrrolidinyl ring, optionally substituted by methyl. Especially, R^a and R³ form

where * indicates the nitrogen atom to which R^a is attached and ** indicates the carbon atom to which R³ is attached.

In another embodiment, R⁴ is hydrogen, Ci-₆alkyl, (CH₂)o-₃C₃_₈cycloalkyl, (CH₂)₀-₃phenyl or Ci_₆alkoxy, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, Ci_₆alkyl, NO₂ or CN, where R⁶ is as hereinbefore defined. Preferably, R is hydrogen, Ci-₆alkyl or Ci-₆alkoxy, optionally substituted by halo or OR⁶, where R⁶ is as hereinbefore defined. More preferably, R⁴ is hydrogen or Ci_ ₆alkyl, optionally substituted by halo. Most preferably, R⁴ is hydrogen or Ci_₄alkyl, optionally substituted by fiuoro or chloro. Especially, R⁴ is hydrogen or Ci_₂alkyl, optionally substituted by fiuoro. Examples of suitable R⁴ groups include hydrogen, methyl, CF₃ and CF₂CF₃ In another embodiment, R⁵ is hydrogen, halo, hydroxy, C^aUcyl, Ci_₆alkoxy, C₃-₈cycloalkyl, aryl or heteroaryl, optionally substituted by N(R⁶)₂. Preferably, R⁵ is hydrogen, Ci_ ₆alkyl, C₃_₈cycloalkyl, phenyl or thiazolyl, optionally substituted by NHR⁶. More preferably, R⁵ is hydrogen, Ci^alkyl, phenyl or thiazolyl, where thiazolyl is optionally substituted by NHR⁶. Most preferably, R⁵ is hydrogen, phenyl or

When R⁵ is other than hydrogen, preferably it is attached to the carbon atom adjacent to the nitrogen atom of the pyridinyl, pyrrolidinyl or pyrimidinyl moiety.

In another embodiment, each W is independently halo, OR⁶, C^aUcyl, CF₃, CO₂R⁶, CON(R⁶)₂, COR⁶ or NR⁶C(O)R⁶, where R⁶ is as hereinbefore defined. Preferably, each W is independently halo, OR⁶, CF₃, CO₂R⁶ or CONHR⁶, where R⁶ is as hereinbefore defined. More preferably, each W is independently fluoro, chloro, OCi-₆alkyl or CF₃. Most preferably, each W is independently OCi^alkyl or CF₃. Especially, each W is independently OCi_-2alkyl. Most especially, W is methoxy.

In another embodiment, Z is a bond when A is pyridinyl or pyrimidinyl. In another embodiment, Z is C=O when A is pyrrolidinyl. Preferably, Z is attached to the nitrogen atom of the pyrrolidinyl moiety. In another embodiment, Z is -CH₂- when ring B is biphenyl.

In another embodiment, M is C₂_8alkylene or C₂-salkenylene, optionally substituted by halo, Ci-₄alkyl or C₃_₆cycloalkyl, and optionally containing O. Preferably, M is C₄_₇alkylene or C₄. ₇alkenylene, optionally substituted by fluoro, chloro or Ci^alkyl, and optionally containing O. More preferably, M is Cs^alkylene or Cs^alkenylene, optionally substituted by fluoro or methyl, and optionally containing O. Examples of suitable M groups include pentylene, hexylene, heptylene,

In another embodiment, ring A is pyridinyl or pyrrolidinyl.

In another embodiment of the present invention, there is provided the compound of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴ and M are as defined in relation to formula (I).

Preferably, R¹ is C(O)NR⁶SO₂R⁶ where R⁶ is as defined in relation to formula (I). More preferably, R¹ is C(O)NHSO₂R⁶ where R⁶ is as defined in relation to formula (I). Most preferably, R¹ is C(O)NHSO₂-C₃-₆cycloalkyl. Especially R¹ is C(O)NHSO₂-cyclopropyl.

Preferably, R² is C₂_₆alkenyl. More preferably, R² is -CH=CH₂.

Preferably, R³ is Ci-₆alkyl or (CH₂)o-₃C₃_₈cycloalkyl, optionally substituted by halo. More preferably, R³ is Ci_₄alkyl or C₃_₆cycloalkyl, optionally substituted by fiuoro or chloro. Most preferably, R³ is Ci_₄alkyl or C₅-₆cycloalkyl, optionally substituted by fiuoro. Especially, R³ is 'propyl, cyclopentyl or CF₃.

Preferably, R⁴ is hydrogen, halo, hydroxy, Ci-₆alkyl, Ci-₆alkoxy, C₃_₈cycloalkyl or phenyl, optionally substituted by halo or OR⁶, where R⁶ is as hereinbefore defined. More preferably, R⁴ is hydrogen, Ci-₆alkyl or C₃_₈cycloalkyl, optionally substituted by halo. Most preferably, R⁴ is hydrogen or Ci_₄alkyl, optionally substituted by fiuoro or chloro. Especially, R⁴ is hydrogen or Ci_₂alkyl, optionally substituted by fiuoro. More especially, R⁴ is hydrogen, methyl or CF₃.

Preferably, M is C₃_i₂alkylene or C₃_i₂alkenylene, optionally substituted by halo or Ci_ ₆alkyl. More preferably, M is C₄_₈alkylene or C₄-8alkenylene, optionally substituted by fiuoro or Ci-₄alkyl. Most preferably, M is C6-7alkylene or C6-7alkenylene, optionally substituted by Ci_₂alkyl. Especially, M is hexylene or

In another embodiment of the present invention, there is provided the compound of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴ and M are as defined in relation to formula (I).

Preferably, R¹ is CO₂R⁶ or C(O)NR⁶SO₂R⁶ where R⁶ is as defined in relation to formula (I). More preferably, R¹ is CO₂R⁶ or C(O)NHSO₂R⁶ where R⁶ is as defined in relation to formula (I). Most preferably, R¹ is CO₂H or C(O)NHSO₂-C₃-₆cycloalkyl. Especially R¹ is CO₂H or C(O)NHSO₂-cyclopropyl. Preferably, R² is Ci_₄alkyl or C₂_₄alkenyl. More preferably, R² is Ci_₂alkyl or -CH=CH₂.

Most preferably, R² is ethyl or -CH=CH₂.

Preferably, R³ is Ci-₆alkyl or (CH₂)₀-3C₃-8cycloalkyl, optionally substituted by halo. More preferably, R³ is Ci_₄alkyl or C₃_₆cycloalkyl, optionally substituted by fiuoro or chloro. Most preferably, R³ is Ci_₄alkyl or C₅-₆cycloalkyl, optionally substituted by fiuoro. Especially, R³ is methyl, 'propyl, 'butyl, CF₃, cyclopentyl or cyclohexyl.

Preferably, R^a is hydrogen or Ci_₂alkyl. More preferably, R^a is hydrogen or methyl. Preferably, R^a and R³ are joined to form a 5- or 6-membered heterocycle containing 1 or 2 N atoms, which heterocycle is optionally substituted by Ci_₄alkyl. More preferably, R^a and R³ are joined to form a 5- or 6- membered heterocycle containing one N atom, which heterocycle is optionally substituted by Ci_₄alkyl. Most preferably, R^a and R³ are joined to form a pyrrolidinyl or a piperidinyl ring, optionally substituted by Ci_₂alkyl. Especially, R^a and R³ are joined to form a

pyrrolidinyl ring, optionally substituted by methyl. More especially, R^a and R³ form

where * indicates the nitrogen atom to which R^a is attached and ** indicates the carbon atom to which R³ is attached. Preferably, R⁴ is hydrogen, halo, hydroxy, C^aUcyl, Ci_6alkoxy, Cs-scycloalkyl or phenyl, optionally substituted by halo or OR⁶, where R⁶ is as hereinbefore defined. More preferably, R⁴ is hydrogen, Ci-₆alkyl or C₃-₈cycloalkyl, optionally substituted by halo. Most preferably, R⁴ is hydrogen or Ci^alkyl, optionally substituted by fiuoro or chloro. Especially, R⁴ is hydrogen or Ci_₂alkyl, optionally substituted by fiuoro. More especially, R⁴ is hydrogen, methyl, CF₃ or CF₂CF₃.

Preferably, M is C₂-8alkylene or C₂-8alkenylene, optionally substituted by halo or C^aUcyl. More preferably, M is C4_7alkylene or C4_7alkenylene, optionally substituted by fiuoro, chloro or Ci-4alkyl. Most preferably, M is Cs^alkylene or Cs^alkenylene, optionally substituted by fiuoro or Ci-₂alkyl. Especially, M is pentylene, hexylene,

In another embodiment of the present invention, there is provided the compound of formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴ and M are defined in relation to formula (I).

Preferably, R¹ is C(O)NR⁶SO₂R⁶ where R⁶ is as defined in relation to formula (I). More preferably, R¹ is C(O)NHSO₂R⁶ where R⁶ is as defined in relation to formula (I). Most preferably, R¹ is C(O)NHSO₂-C₃_₆cycloalkyl. Especially, R¹ is C(O)NHSO₂-cyclopropyl.

Preferably, R² is C_2-6alkenyl. More preferably, R² is -CH=CH₂.

Preferably, R³ is Ci-₆alkyl or (CH₂)o-₃C₃_₈cycloalkyl, optionally substituted by halo. More preferably, R³ is Ci^alkyl or C₃_₆cycloalkyl. Most preferably, R³ is C^alkyl or Cs-oCycloalkyl. Especially, R³ is 'butyl or cyclohexyl. Preferably, R⁴ is hydrogen or d-₆alkyl. More preferably, R⁴ is hydrogen or Ci_₄alkyl. Most preferably, R⁴ is hydrogen or Ci_-2alkyl. Especially, R⁴ is hydrogen.

Preferably, M is C₂-8alkylene pr C₂-8alkenylene, optionally substituted by halo or C^aUcyl. More preferably, M is C3-7alkylene or C3-7alkenylene, optionally substituted by Ci_₄alkyl. Most preferably, M is C₄-6alkenylene or C₄-6alkenylene, optionally substituted by Ci_₂alkyl. Especially, M is pentylene or

In another embodiment of the present invention, there is provided the compound of formula (Id):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, M and W are defined in relation to formula (I).

Preferably, R¹ is C(O)NR⁶SO₂R⁶ where R⁶ is as defined in relation to formula (I). More preferably, R¹ is C(O)NHSO₂R⁶ where R⁶ is as defined in relation to formula (I). Most preferably, R¹ is C(O)NHSO₂-C₃-6cycloalkyl. Especially, R¹ is C(O)NHSO₂-cycopropyl.

Preferably, R² is C₂_₆alkenyl. More preferably, R² is -CH=CH₂

Preferably, R³ is Ci_₆alkyl or (CH₂)₀-₃C₃_₈cycloalkyl, optionally substituted by halo. More preferably, R³ is Ci_₄alkyl or Cs-όCycloalkyl. Most preferably, R³ is C₃-₄alkyl or Cs-όCycloalkyl. Especially, R³ is cyclohexyl.

Preferably, R⁴ is hydrogen or Ci-6alkyl. More preferably, R⁴ is hydrogen or Ci_₄alkyl. Most preferably, R⁴ is hydrogen or Ci_₂alkyl. Especially, R⁴ is hydrogen.

Preferably, R⁵ is hydrogen, halo, hydroxy, Ci-₆alkyl, Ci-₆alkoxy, C₃-₈cycloalkyl, aryl or heteroaryl. More preferably, R⁵ is hydrogen, C^aUcyl, C₃_₈cycloalkyl or aryl. Most preferably, R⁵ is hydrogen, Ci_₄alkyl, C₃-6cycloalkyl or phenyl. Especially, R⁵ is hydrogen, Ci_₂alkyl, C₅- ₆cycloalkyl or phenyl. More especially, R⁵ is phenyl. Preferably, W is halo, OR⁶, d_₆alkyl, CF₃, CO₂R⁶, CON(R⁶)₂, COR⁶ Or NR⁶C(O)R⁶, where R⁶ is as hereinbefore defined. More preferably, W is fiuoro, chloro, 0Ci_6alkyl, CF₃, CO₂Ci_₆alkyl, or CONHC_1-6alkyl. Most preferably, W is fiuoro, chloro, OCi_₄alkyl or CF₃. Especially, W is OCi_₂alkyl. More especially, W is methoxy.

Preferably, M is C₃_i₂alkylene or C₃_i₂alkenylene, optionally substituted by halo or Ci- ₆alkyl. More preferably, M is C4_8alkylene or C4_8alkenylene, optionally substituted by fiuoro or Ci_₄alkyl. Most preferably, M is C₆-7alkylene or C₆-7alkenylene, optionally substituted by Ci_₂alkyl. Especially, M is hexylene, heptylene,

When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence. As used herein, the term "alkyl" as a group or part of a group refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range. Thus, for example, "Ci_6alkyl" refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl. As another example, "Ci^alkyl" refers to n-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl. The term "alkoxy" represents any linear or branched chain alkyl group having a number of carbon atoms in the specified range and attached through an oxygen bridge. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy and t-butoxy.

The term "alkenyl" as a group or part of a group refers to any linear or branched chain alkyl group containing at least one double bond, which may occur at any point along the chain, and having a number of carbon atoms in the specified range. E- and Z- forms are both included, where applicable. Examples of suitable alkenyl groups include vinyl, allyl, butenyl and pentenyl.

The term "cycloalkyl" refers to any cyclic alkyl ring having a number of carbon atoms in the specified range. Examples of suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The terms "alkylene" and "alkenylene" as a group or part of a group refer to the groups "alkyl" and "alkenyl" respectively, when they are divalent, i.e. attached at two atoms.

The term "halogen" or "halo" means fluorine, chlorine, bromine and iodine (alternatively referred to as fiuoro, chloro, bromo and iodo, respectively). The term "aryl" as a group or part of a group means a carbocyclic aromatic ring. Examples of suitable aryl groups include phenyl and naphthyl.

The term "Het" as a group or part of a group means a 5- to 7-membered saturated or unsaturated non-aromatic ring having 1 to 4 heteroatoms selected from N, O and S. The term "heteroaryl" as a group or part of a group means a 5- to 10-membered heteroaromatic ring system containing 1 to 4 heteroatoms selected from N, O and S. Examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, benzothienyl, benzimidazolyl, benzofuryl, quinolyl and isoquinolyl. Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaryl ring described as containing from "1 to 3 heteroatoms" means the ring can contain 1, 2, or 3 heteroatoms.

Where a compound or group is described as "optionally substituted" one or more substituents may be present. Furthermore, optional substituents may be attached to the compounds or groups which they substitute in a variety of ways, either directly or through a connecting group of which the following are examples: amine, amide, ester, ether, thioether, sulfonamide, sulfamide, sulfoxide, urea, thiourea and urethane. As appropriate an optional substituent may itself be substituted by another substituent, the latter being connected directly to the former or through a connecting group such as those exemplified above. Specific compounds within the scope of this invention include those named in the

Examples and Table hereinbelow and their pharmaceutically acceptable salts.

For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin. The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfate ester, or reduction or oxidation of a susceptible functionality.

The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.

The present invention also includes within its scope any enantiomers, diastereomers, geometric isomers and tautomers of the compounds of formula (I). It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the invention.

The preferred compounds of the present invention will have the stereochemistry as shown in formula (Ie):

The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

In another aspect, the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment or prevention of infection by hepatitis C virus in a human or animal.

A further aspect of the invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. The composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally.

The pharmaceutical compositions optionally also include one or more other agents for the treatment of viral infections such as an antiviral agent, or an immunomodulatory agent such as α-, β- or γ-interferon.

In a further aspect, the invention provides a method of inhibiting hepatitis C virus protease and/or of treating or preventing an illness due to hepatitis C virus, the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition described above or of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. "Effective amount" means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.

The term "subject" (alternatively referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The dosage rate at which the compound is administered will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy. Suitable dosage levels may be of the order of 0.02 to 5 or 10 g per day, with oral dosages two to five times higher. For instance, administration of from 10 to 50 mg of the compound per kg of body weight from one to three times per day may be in order. Appropriate values are selectable by routine testing. The compound may be administered alone or in combination with other treatments, either simultaneously or sequentially. For instance, it may be administered in combination with effective amounts of antiviral agents, immunomodulators, anti-infectives or vaccines known to those of ordinary skill in the art. It may be administered by any suitable route, including orally, intravenously, cutaneously and subcutaneously. It may be administered directly to a suitable site or in a manner in which it targets a particular site, such as a certain type of cell. Suitable targeting methods are already known.

An additional aspect of the invention provides a method of preparation of a pharmaceutical composition, involving admixing at least one compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents.

As noted above, the present invention also relates to a method of inhibiting HCV NS3 protease, inhibiting HCV replication, or preventing or treating HCV infection with a compound of the present invention in combination with one or more therapeutic agents and a pharmaceutical composition comprising a compound of the present invention and one or more therapeutic agents selected from the group consisting of a HCV antiviral agent, an immunomodulator, and an anti- infective agent. Such therapeutic agents active against HCV include ribavirin, levovirin, viramidine, thymosin alpha- 1, interferon-β, interferon-α, pegylated interferon-α (peginterferon-α), a combination of interferon-α and ribavirin, a combination of peginterferon-α and ribavirin, a combination of interferon-α and levovirin, and a combination of peginterferon-α and levovirin. Interferon-α includes recombinant interferon-α2a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, NJ), pegylated interferon-α2a (Pegasys™), interferon-α2b (such as Intron-A interferon available from Schering Corp., Kenilworth, NJ), pegylated interferon-α2b (Peglntron™), a recombinant consensus interferon (such as interferon alphacon-1), and a purified interferon-α product. Amgen's recombinant consensus interferon has the brand name Infergen®. Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin. Viramidine represents an analog of ribavirin disclosed in WO 01/60379 (ICN Pharmaceuticals). In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.

For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease. HCV NS3 protease inhibitors are disclosed in WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, GB- 2337262, WO 02/48116, WO 02/48172, and U.S. Patent No. 6,323,180.

Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (IMPDH). Thus, inhibition of IMPDH represents another useful target for the discovery of inhibitors of HCV replication. Therefore, the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497, disclosed in WO 97/41211 and WO 01/00622 (Vertex); another IMPDH inhibitor, such as that disclosed in WO 00/25780 (Bristol-Myers Squibb); or mycophenolate mofetil [see A.C. Allison and E.M. Eugui, Agents Action. 44 (Suppl): 165 (1993)].

For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane) [see J. Kirschbaum, Anal. Profiles Drug Subs. 12: 1-36 (1983)].

The compounds of the present invention may also be combined for the treatment of HCV infection with antiviral 2'-C-branched ribonucleosides disclosed in R. E. Harry-O'kuru, et al., J₁ Org. Chem.. 62: 1754-1759 (1997); M. S. Wolfe, et al.. Tetrahedron Lett.. 36: 7611-7614 (1995); U.S. Patent No. 3,480,613; WO 01/90121; WO 01/92282; WO 02/32920; WO

04/002999; WO 04/003000; and WO 04/002422. Such 2'-C-branched ribonucleosides include 2'-C-methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine, 2'-C-methyl-guanosine, and 9- (2-C-methyl-β-D-ribofuranosyl)-2,6-diaminopurine, and the corresponding amino acid ester of the ribose C-2', C-3', and C-5' hydroxyls and the corresponding optionally substituted cyclic 1,3- propanediol esters of the 5 '-phosphate derivatives.

The compounds of the present invention may also be combined for the treatment of HCV infection with other nucleosides having anti-HCV properties, such as those disclosed in WO 02/51425 (Mitsubishi Pharma Corp.); WO 01/79246, WO 02/32920 and WO 02/48165 (Pharmasset, Ltd.); WO 01/68663 (ICN Pharmaceuticals); WO 99/43691; WO 02/18404 (Hoffmann-LaRoche); U.S. 2002/0019363; WO 02/100415; WO 03/026589; WO 03/026675; WO 03/093290; US 2003/0236216; US 2004/0006007; WO 04/011478; WO 04/013300; US 2004/0063658; and WO 04/028481. For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS5B polymerase. Such HCV NS5B polymerase inhibitors that may be used as combination therapy include those disclosed in WO 02/057287, US 6,777,395, WO 02/057425, US 2004/0067901, WO 03/068244, WO 2004/000858, WO 04/003138 and WO 2004/007512. Other such HCV polymerase inhibitors include valopicitabine (NM-283; Idenix) and 2'-F-2'-beta-methylcytidine (see also WO 2005/003147, assigned to Pharmasset, Ltd.).

The compounds of the present invention may also be combined for the treatment of HCV infection with non-nucleoside inhibitors of HCV polymerase such as those disclosed in WO 01/77091 (Tularik, Inc.); WO 01/47883 (Japan Tobacco, Inc.); WO 02/04425 (Boehringer Ingelheim); WO 02/06246, WO 03/062211, WO 2004/087714, WO 2004/110442, WO 2005/034941, WO 2005/023819, WO2006/029912, WO 2006/008556, WO 2006/027628, GB2430621, WO2006/046030, WO2006/046039, WO2006/119975, WO2007/028789 and WO2007/029029 (all Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A.); WO 02/20497; WO 2005/016927 (in particular JTK003), and WO 2005/080399 (Japan Tobacco, Inc.); WO 2006/020082 (Bristol-Myers Squibb Company); and HCV-796 (Viropharma Inc.).

The present invention also provides a process for the preparation of compounds of formula (I).

According to a general process (a), compounds of formula (I) may be prepared by the coupling of the ester of formula (II) with the amine of formula (III):

where m, n, R¹, R², R³, R⁴, R⁵, R^a, M, W, Z and ring B are as defined in relation to formula (I) and P¹ is Ci_6alkyl, such as methyl. The ester (II) is first hydrolysed under standard conditions (e.g. in the presence of a base, such as lithium hydroxide, in a solvent, such as THF/water, MeOH/water or dioxane/water) to give the free acid. The coupling reaction is then conveniently carried out in the presence of a coupling reagent, such as TBTU or HATU, and a base, such as diisopropylethylamine or triethylamine, in a solvent. Suitable solvents include DMF and dichloromethane. Optionally, a dehydrating agent, such as DMAP, may also be used.

The compound of formula (II) where M has 4 or more carbon atoms in the tether and one or more double bonds may be prepared by the internal ring closure of the diene of formula (IV):

where n, R³, R⁴, R⁵, R^a, W, Z and ring B are as defined in relation to formula (I), P¹ is as defined in relation to formula (II) and M' is a suitable precursor moiety of group M in formula (II) which can be converted into the corresponding moiety of M during the ring closure or after it using methods described in the accompanying Schemes and Examples or known to the person skilled in the art. The reaction is conveniently carried out in the presence of a metathesis catalyst, such as Zhan catalyst [dichloro(5-chloro-2-isopropoxy benzylidene)(l,3-dimethylimidazolidin-2- ylidene)ruthenium], preferably at raised temperature or under microwave irradiation, in a suitable solvent such as dichloromethane or 1,2-dichloroethane. The resultant ring double bond may be hydrogenated to give a further compound of formula (II). The hydrogenation is preferably carried out in the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as methanol or methanol/ethyl acetate mixture. Compounds of formulae (II), (III) and (IV) are either well known in the art or may be prepared by conventional methodology well known to one of ordinary skill in the art using, for instance, procedures described in the accompanying Schemes and Examples, or by alternative procedures which will be readily apparent.

Further details of suitable procedures will be found in the accompanying Schemes and Examples. For instance compounds of formula (I) can be converted into other compounds of formula (I) using synthetic methodology well known in the art.

Thus, for instance, the compound of formula (I) where M is unsaturated may be converted into the compound of formula (I) where M is saturated by hydrogenation, preferably in the presence of a suitable catalyst, such as palladium on carbon, in a suitable solvent, such as methanol/ethyl acetate mixture.

Furthermore, the compound of formula (I) where R^a is Ci^alkyl may be prepared from the compound of formula (I) where R^a is hydrogen by alkylation. The reaction may be carried out in the presence of a mild base, such as sodium cyanoborohydride, and a catalyst, such as zinc (II) chloride, in a suitable solvent, such as methanol. The alkyl source is formaldehyde or CH₃(CH₂V₂CHO.

During any of the described synthetic sequences, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3^rd ed., 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The compounds of the present inventions are useful in the inhibition of HCV protease (e.g., HCV NS3 protease) and the prevention or treatment of infection by HCV. For example, the compounds of this invention are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.

The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HCV protease, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. The HCV NS3 protease inhibitory activity of the present compounds may be tested using assays known in the art. One such assay is HCV NS3 protease time-resolved fluorescence (TRF) assay as described as follows:

HCV NS3 protease time-resolved fluorescence (TRF) assay

The NS3 protease TRF assay was performed in a final volume of lOOμl in assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15 % glycerol, 0.15 % Triton X-IOO, 10 mM DTT, and 0.1 % PEG 8000. The NS3 protease was pre-incubated with various concentrations of inhibitors for 10-30 minutes. The peptide substrate for the assay is Ac-C(Eu)-DDMEE- Abu- [COO]- XSAK(QSY7)-NH2, where Eu is an europium-labeled group, Abu is 1-aminobutanoic acid which connects an ester linkage with 2-hydroxy propanoic acid (X). Hydrolysis of the peptide by NS3 protease activity causes in separation of the fiuorophore from the quencher, resulting in an increase in fluorescence. Activity of the protease was initiated by adding the TRF peptide substrate (final concentration 50-100 nM). The reaction was quenched after 1 hour at room temperature with 100 μl of 500 mM MES, pH 5.5. Product fluorescence was detected using either a Victor V2 or Fusion fluorimeter (Perkin Elmer Life and Analytical Sciences) with excitation at 340 nm and emission at 615 nm with 50-400 μs delay. Testing concentrations of different enzyme forms was selected with a signal to background ratio of 10-30. The inhibition constants were derived using a four-parameter fit.

Other examples of such assays are described in e.g., International patent publication WO2005/046712. Compounds useful as HCV NS3 protease inhibitors would have a Ki less than 50 μM, more preferably less than 10 μM, most preferably less than 1 μM, especially less than 100 nM, and more especially less than 50 nM. The following schemes and examples serve to illustrate the invention and its practice.

¹H NMR spectra were recorded on Bruker AM series spectrometers operating at (reported) frequencies between 300 and 600 MHz. Chemical shifts (δ) for signals corresponding to non-exchangeable protons (and exchangeable protons where visible) are recorded in parts per million (ppm) relative to tetramethylsilane and are measured using the residual solvent peak as reference. Signals are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad, and combinations thereof); coupling constant(s) in Hertz (Hz); number of protons. Mass spectral (MS) data were obtained on a Perkin Elmer API 100, or Waters MicroMass ZQ, operating in negative (ES^") or positive (ES⁺) ionization mode and results are reported as the ratio of mass over charge (m/z). Preparative scale HPLC separations were carried out on a Waters Micromass System incorporating a 2525 pump module, a Micromass ZMD detector and a 2767 collection module, under Fraction Linx software or on a Shimadzu preparative system.

The following abbreviations are used in the examples, the schemes and the tables: AcOH: acetic acid; dioxan(e): 1,4-dioxane; DIPEA or ¹Pr₂NEt: diisopropylethylamine; DCE: 1,2- dichloroethane; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMF: N, N- dimethylformamide; DMSO: dimethylsulfoxide; EDC: l-(3-dimethylaminopropyl)-3- ethylcarbodiimide; Et₂O: diethyl ether; EtOAc: ethyl acetate; eq.: equivalent(s); h: hour(s); HATU: O-(7-azabenzotriazol-l-yl)-Λ/,Λ/_>N',N'-tetramethyluronium hexafluorophosphate; MeCN: acetonitrile; MeOH: methanol; min: minute(s); MS: mass spectrum; MTBE: tert Butyl methyl ether; PCC: pyridinium chlorochromate; PE: petroleum ether 30/60; quant.: quantitative; RP- HPLC: reversed phase high-performance liquid chromatography; RP-MS-HPLC: mass-guided reversed phase high-pressure liquid chromatography; RT: room temperature; sat. aq.: saturated aqueous; TBTU: O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate; TEA: triethylamine; THF: tetrahydrofuran.

Scheme 1

Compound 1: (5R,7S,10S,12R or S)-N-((lR,25)-l-{[(cyclopropylsulfonyl)amino]carbonyl}- 2-vinylcyclopropyl)-10-isopropyl-3,9-dioxo-12-(trifluoromethyl)- 6,7,9,10,ll,12,13,14,15,16,17,18-dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,ll- benzoxatriazacycloicosine-7-carboxamide

Step 1: (46^f)-4-isopropyl-2-(trifluoromethyl)-l,3-oxazolidine 40 (R³ = isopropyl) The oxazolidine 40 was obtained as a 7:3 mixture of diastereoisomers prepared as described in Organic Letters 2004, 641. Step 2: (25V3-methyl-2- ([(Ii? or y)-l-(trifluoromethyl)hept-6-en-l-yl1aminoibutan-l-ol 41a (R³ = isopropyl)

A small amount of a solution (3M) of 6-bromohex-l-ene in dry Et₂O was added dropwise to magnesium turnings (1 eq.). A small crystal of iodine was added followed by the remainder of the bromide solution. The reaction mixture was cooled to -78°C and (4S)-4-isopropyl-2-

(trifluoromethyl)-l,3-oxazolidine 40 (1 eq.) dissolved in Et₂O (3M) was added dropwise. The reaction mixture was stirred at 0⁰C for Ih and then quenched with aqueous HCl (IN). Aqueous NaOH (IN) was added until pH = 7. The two layers were separated and the aqueous phase was diluted with brine and extracted with CH₂Cl₂. The organic layers were joined, washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/PE gradient from 5:95 to 20:80) to afford the title compound as a mixture of two diastereoisomers (50%) that were separated by RP-HPLC (stationary phase: column Waters Symmetry prep. C18, 7 μm, 19 x 300 mm, mobile phase: MeCN/H₂O containing 0.1 % TFA). Fractions containing the desired compounds as pure diastereoisomers were combined and freeze dried to afford 41a (second eluting) and 41b (first eluting) (67%, 41a : 41b = 1 : 0.14).

41a) ¹H NMR (300 MHz, CDCl₃, 300 K) δ 5.75 (ddt, J 17.0, 10.2, 6.7, IH), 5.47-5.17 (bs, IH), 5.06-4.90 (m, 2H), 3.96-3.70 (m, 3H), 3.24-3.09 (m, IH) 2.13-1.74 (m, 5H), 1.60-1.34 (m, 4H), 1.07 (d, J 6.9, 3H), 1.01 (d, J 6.9, 3H). MS (ES⁺) m/z 268 (M+H)⁺.

Step 3: f26^f)-3-methyl-2-{[(li? or S)-I -(trifluoromethyl)hept-6-en-l-vH amino jbutanoic acid 42a (R³ = isopropyl)

To a solution (0.13 M) of (25)-3-methyl-2-{[l-(trifluoromethyl)hept-6-en-l-yl]amino}butan-l-ol 41a in acetone cooled to 0⁰C, Jones reagent (8N) (5 eq.) was added. The reaction mixture was stirred at 0⁰C for 15 min at RT overnight then was diluted with water and stirred at RT for 20 min. Aqueous NaOH (IN) was added to reach pH=5 and the mixture was extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo to afford the crude product, which was used in the following step without further purification. MS (ES⁺) m/z 282 (M+H)⁺.

Step 4: methyl N-F(IR or ^-l-(trifluoromethyl)hept-6-en-l-yll-L-valyl-(4i?)-4-(r(4-vinyl-1.3- dihvdro-2H-isoindol-2-yl)carbonyl1oxy}-L-prolinate 44a (R³ = isopropyl)

To a stirred mixture of (25)-3-methyl-2-{[(lR or 5)-l-(trifluoromethyl)hept-6-en-l- yl] amino }butanoic acid 42a in CH₂Cl₂ (0.09M) were added /Pr₂EtN (2.4 eq.), TBTU (1.2 eq.) and after 5 min (25^*,4i?)-2-(methoxycarbonyl)-4-{[(4-vinyl-l,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}pyrrolidinium chloride 43 (1 eq.). The mixture was stirred at RT overnight. Aqueous HCl (IN) was added, the organic layer was separated and washed with sat. aq. NaHCO₃ and brine, dried over Na₂SO₄ and filtered. Evaporation under reduced pressure afforded a residue, which was purified by flash chromatography on silica gel (EtOAc/PE gradient from 5:95 to 15:85) to afford compound 44a as a white foam (24% after two steps). MS (ES⁺) m/z 580 (M+H)⁺.

Step 5: methyl (5R.75U 05.12R or S.17£yiO-isopropyl-3.9-dioxo-12-(trifluoromethviy 6.7.9.10.1 U2.13.14.15.16-decahydro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacvcloicosine-7-carboxylate 45a (R³ = isopropyl)

Zhan catalyst I (0.15 eq.) was added to methyl N-[I -(trifluoromethyl)hept-6-en-l-yl]-L-valyl- (4R)-4-{[(4-vinyl-l,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate 44a in DCE (0.016 M) and the mixture was refiuxed for 45 min. Volatiles were evaporated under reduced pressure affording a residue, which was used in the following step without further purification. MS (ES⁺) m/z 552 (M+Η)⁺.

Step 6: methyl (5^75.105.12Jg or 5V10-isopropyl-3.9-dioxo-12-(trffluoromemylV 6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacycloicosine-7-carboxylate 46a (R³ = isopropyl)

Palladium 10% on carbon (20% w/w) and methyl (5R,7S,\0S,\2R or 5^*,17E)-10-isopropyl-3,9- dioxo-12-(trifiuoromethyl)-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8-dimethano- 4,2,8,1 l-benzoxatriazacycloicosine-7-carboxylate 45a in methanol (0.035M) were stirred under a hydrogen atmosphere overnight. Solids were filtered over celite and the resulting solution was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc/PE gradient from 1:9 to 3:7) to afford compound 46a as a white foam (70% over two steps). MS (ES⁺) m/z 554 (M+H)⁺.

Step 7: (5RJSΛ0SΛ2R or ^-10-isopropyl-3.9-dioxo-12-(trifluoromethyl)- 6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacvcloicosine-7-carboxylic acid 47a (R³ = isopropyl)

Lithium hydroxide (3 eq.) was added to a stirred mixture of methyl (5R,7S,10S, \2R or 5)-10- isopropyl-3,9-dioxo-12-(trifluoromethyl)-6,7,9,10,l l,12,13,14,15,16,17,18-dodecahydro-lH,5H- 2,22:5, 8-dimethano-4,2, 8,1 l-benzoxatriazacycloicosine-7-carboxylate 46a in THF and water (2/1 v/v, 0.01 M) and the mixture was stirred at RT overnight. Aqueous HCl (IN) was added to reach pH = 6 and the mixture extracted with EtOAc. The organic layer was separated, dried over Na₂SO₄, filtered and concentrated to obtain the crude product 47a which was used in the following step without further purification. MS (ES⁺) m/z 540 (M+H)⁺.

Step 8: (5RJSΛ0SΛ2R or ^-N-rdR^^-l-irrcvclopropylsulfonvnaminoicarbonvU^- vinylcvclopropyD-lO-isopropyl-S^-dioxo-^-αrifluoromethvD-όJ^.lO.l l.^.n.M.lS.lό.π.lδ- dodecahvdro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide 1 To a stirred mixture of (5i?, 75,105)- 10-isopropyl-3, 9-dioxo-l 2-(trifluoromethyl)- 6,7,9,10,11, 12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l- benzoxatriazacycloicosine-7-carboxylic acid 47a in CH2CI2 (5mM) were added /-Pr₂EtN (2.4 eq), TBTU (1.2 eq.) and after 5 min (li?,25)-l-{[(cyclopropylsulfonyl)amino]carbonyl}-2- vinylcyclopropanaminium chloride 48 (prepared as described in WO 03/099274) (1.2 eq.). The mixture was stirred at RT overnight. The reaction mixture was extracted with aqueous HCl (IN), sat. aq. NaHCC>3 and brine, dried over Na₂SO₄ and filtered. Evaporation under reduced pressure afforded a residue, which was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 urn, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford compound 1 as a white powder (34 %). ¹H NMR (600 MHz, DMSO-d₆, 300 K) δ 10.57 (s, IH), 9.22 (s, IH), 7.24 (t, J 7.5, IH), 7.18 (d, J 7.5, IH), 7.11 (d, J 7.5, IH), 5.68 (ddd, J 17.2, 10.0, 9.6, IH), 5.42 (bt, IH), 5.28 (dd, J 17.2, 1.5, IH), 5.12 (dd, J 10.4, 1.7, IH), 4.67-4.56 (m, 4H), 4.40 (dd, J 11.0, 6.5, IH), 3.96 (d, J 10.3, IH), 3.76 (dd, J 11.7, 3.1, IH), 3.31 (d, J 6.3, IH), 2.92-2.86 (m, IH), 2.92-2.30 (m, IH), 2.55-2.50 (partially obscured by residual DMSO, IH), 2.47-2.40 (m, IH), 2.22 (dd, J 13.8, 6.4, IH), 2.16 (q, J 8.8, IH), 2.09-2.02 (m, IH), 1.79-1.71 (m, 2H), 1.57-1.46 (m, 3H), 1.44-1.18 (m, 8H), 1.13-1.07 (m, IH), 1.06-0.98 (m, 3H), 0.91 (d, J 6.6, 3H), 0.83 (d, J 6.6, 3H). ¹³C NMR (600 MHz, DMSO-d₆, 300 K) δ 174.08, 172.16, 169.17, 152.92, 137.09, 136.23, 135.00, 133.37, 127.93, 127.57, 126.04, 120.32, 117.87, 73.50, 64.83, 59.03, 58.87, 53.23, 52.12, 50.67, 40.79, 34.59, 33.81, 31.42, 31.17, 30.74, 28.90, 28.48, 26.43, 26.02, 23.47, 22.76, 19.09, 17.93, 5.73, 5.36. MS (ES⁺) m/z 752 (M+H)⁺.

Scheme 2

Scheme 3

Scheme 4

Scheme 5

Scheme 6

Compounds 10 and 25:

10) (5R,7S,IOS,12R or 5)-N-((lR,2S)-l-{[(cyclopropylsulfonyl)amino]carbonyl}-2- vinylcyclopropyl)-10-isopropyl-12-methyl-3,9-dioxo-6,7,9,10,ll,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,ll-benzoxatriazacycloicosine-7-carboxamide 25) (5R,7S,IOS,12R or S)-10-cyclohexyl-N-((lR,2S)-l-{[(cyclopropylsulfonyl)amino]carbonyl}- 2-vinylcyclopropyl)-12-methyl-3,9-dioxo-6,7,9,10,ll,12,13,14,15,16,17,18-dodecahydro-lH,5H- 2,22:5,8-dimethano-4,2,8,ll-benzoxatriazacycloicosine-7-carboxamide

Step 1 : N-methoxy-N-methylhept-6-enamide 58 EDC (1.1 eq.) was added in small portions over 1.5 h to a stirred mixture of hept-6-enoic acid, methoxy(methyl)ammonium chloride (1.1 eq.) and DMAP (1.1 eq.) in CH₂Cl₂ (0.2 M). After 14 h, the mixture was diluted with CH₂Cl₂, then washed sequentially with hydrochloric acid (IM), NaOH (IM), brine and dried (Na₂SO₄). Evaporation of the solvent afforded the title compound (97%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃, 300 K) δ 5.87-5.75 (m, IH), 5.01 (d, J 17.1, IH), 4.95 (d, J 10.1, IH), 3.68 (s, 3H), 3.18 (s, 3H), 2.48-2.36 (m, 2H), 2.13-2.04 (m, 2H), 1.71-1.60 (m, 2H), 1.50-1.40 (m, 2H).

Step 2: oct-7-en-2-one 59

Methyl magnesium bromide (3M in ether, 3 eq.) was added dropwise to a stirred mixture of /V- methoxy-7V-methylhept-6-enamide 58 in THF (0.1 M) cooled at 0⁰C. After stirring for 1 h at 0⁰C, the mixture was poured into sat. aq. NH₄Cl and diluted with EtOAc. The aqueous layer was further extracted with EtOAc, the combined organic layers were washed with brine and dried (Na₂SO₄).

Evaporation of the solvent at 30 mbar afforded the title compound (96%) as a colorless oil. ¹H NMR

(400 MHz, CDCl₃, 300 K) δ 5.81 (ddt, J 17.1, 10.3, 6.7, IH), 5.02 (dd, J 17.1, 1.5, IH), 4.97 (d, J 10.3, IH), 2.46-2.43 (m, 2H), 2.15 (s, 3H), 2.10-2.05 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.37 (m,

2H).

Step 3: Methyl (2y)-3-methyl-2-(r(16' and i?)-l-methylhept-6-en-l-yl1aminoibutanoate 60 (R³ = /Pr) A solution OfNaCNBH₃ (1.2 eq.) and ZnCl₂ (0.6 eq.) in methanol (0.3 M with respect to NaCNBH₃) was added dropwise to a solution of L-valine methyl ester hydrochloride (1.1 eq.) and oct-7-en-2- one 59 in methanol (0.5 M). After stirring for 2 days, volatiles were evaporated under reduced pressure and the residue partitioned between CH₂Cl₂ and sat. aq. NaHCO₃. The organic layer was dried (Na₂SO₄) and evaporated under reduced pressure affording the title compounds (57%) as a colorless oil. MS (ES⁺) m/z 242 (M+H)⁺.

Step 3: Methyl (^SVcvclohexyl-ϋYlig and SV l-methylhept-6-en-l-yl)aminolacetate 60 (R³ = cHex) A solution OfNaCNBH₃ (1.2 eq.) and ZnCl₂ (0.6 eq.) in methanol (0.2 M with respect to NaCNBH₃) was added dropwise to a solution of (15)-l-cyclohexyl-2-methoxy-2-oxoethanaminium chloride (1.1 eq.) and oct-7-en-2-one 59 in methanol (0.05 M). After stirring overnight, volatiles were evaporated under reduced pressure and the residue partitioned between CH₂Cl₂ and sat. aq. NaHCO₃. The organic layer was dried (Na₂SO₄) and evaporated under reduced pressure. The title compounds (obtained as a mixture of two diastereoisomers in ratio 7:2) was used in the following step without further purification. MS (ES⁺) m/z 282 (M+H)⁺.

Step 4: (25V3-methyl-2-(rπ<S and liQ-l-methylhept-6-en-l-yllaminoibutanoic acid 61 (R³ = /Pr) Lithium hydroxide monohydrate (3.3 eq.) was added to a stirred mixture of methyl (2S)-3-methyl-2- {[(15^* and i?)-l-methylhept-6-en-l-yl]amino}butanoate 60 in MeOH and water (3/1 v/v, 0.03 M) and the mixture was stirred at reflux. After 22 h it was cooled to RT and MeOH was evaporated under reduced pressure. IN HCl was added until pH = 5, and the aq. phase was extracted with CH₂Cl₂. The organic layers were dried (Na₂SO₄) and evaporated under reduced pressure affording the title compound (65%) as a white solid. MS (ES⁺) m/z 228 (M+H)⁺.

Step 4: (2R and 6^f)-N-r(6^f)-carboxy(cvclohexyl)methylloct-7-en-2-aminium chloride 61 (R³ = cHex) Lithium hydroxide monohydrate (4 eq.) was added to a stirred mixture of methyl (2S)-cyclohexyl- {[(IR and 5)-l-methylhept-6-en-l-yl)amino]acetate 60 in THF and water (3/2 v/v, 0.1 M) and the mixture was stirred at reflux. After 30 h, the mixture was cooled to RT and THF was evaporated under reduced pressure. IN HCl was added until pH = 5, and the aq. phase was extracted with EtOAc. HCl (4N) in dioxane (2 eq.) was added to the organic layers. Drying over Na₂SO₄, filtration and evaporation under reduced pressure afforded the title compounds as mixture of diastereomers that was used in the following step without further purification. MS (ES⁺) m/z 268 (M+H)⁺.

Step 5: (2R and ^-N-{(l^-l-r((2^4i?)-2-(methoxycarbonyl)-4-{r(4-vinyl-1.3-dihvdro-2H-isoindol- 2-yl)carbonylloxy}pyrrolidin-l-yl)carbonyll-2-methylpropyl}oct-7-en-2-aminium trifluoroacetate 62 (R³= /Pr)

/-Pr₂EtN (4 eq.) followed by TBTU (1.2 eq.) were added to a stirred mixture of (2S)-3-methyl-2- {[(15^* and li?)-l-methylhept-6-en-l-yl]amino}butanoic acid 61 and (25^*,4i?)-2-(methoxycarbonyl)-4- {[(4-vinyl-l,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidinium chloride 43 (1 eq.) in CH₂Cl₂ (0.03 M) and the mixture was stirred at RT. After 3.5 h, sat. aq. NaHCO₃ was added, the organic layer was separated and dried (Na₂SO₄). Evaporation under reduced pressure afforded a residue, which was redissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 urn, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compounds were combined and freeze dried to afford the title compounds as a white powder (76 %). MS (ES⁺) m/z 526 (M+H)⁺.

Step 5: (3R.5S)-l-t(2S)-2-cvdohexyl-2-\((lR and ^-l-methylhept-6-en-l-yl)aminolacetyli-5- (methoxycarbonyl)pyrrolidin-3-yl-4-vinyl-l,3-dihvdro-2H-isoindole-2-carboxylate 62 (R³= cHex) /-Pr₂EtN (5eq.) followed by TBTU (1.2 eq.) were added to a stirred mixture of (2R and S)-N-[OS)- carboxy(cyclohexyl)methyl]oct-7-en-2-aminium chloride 61 and (25^*,4i?)-2-(methoxycarbonyl)-4- {[(4-vinyl-l,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidinium chloride 43 (1 eq.) in CH₂CI₂ (0.03 M) and the mixture was stirred at RT overnight. Saturated aq. NaHCC>3 was added, the organic layer was separated and dried (Na₂SO₄). Evaporation under reduced pressure afforded a residue that was purified by flash chromatography on silica gel (EtOAc/PE + 0.05% TEA gradient from 10\90 to 35\65) to afford the title compound as a mixture of two diastereomers (45% over three steps). MS (ES⁺) m/z 566 (M+H)⁺.

Step 6: (5RJSΛ0SΛ2R or SU7£yl0-isopropyl-7-(methoxycarbonylyl2-methyl-3.9-dioxo- 6.7.9.10.11.12.13.14.15.16-decahvdro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacvcloicosin-11-ium trifluoroacetate 63a (R³=/Pr)

Zhan catalyst I (0.2 eq.) was added to (2R and 5)-N-{(15)-l-[((25',4i?)-2-(methoxycarbonyl)-4-{[(4- vinyl-l,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidin-l-yl)carbonyl]-2-methylpropyl}oct-7-en- 2-aminium trifluoroacetate 62 in CH₂Cl₂ (0.016 M) and the mixture was heated under microwave irradiation at 100 ⁰C for 40 min. Undissolved material was filtered away and the resulting solution was evaporated under reduced pressure affording a residue, which was redissolved with DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 um, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA; the title compound 63a was the first diastereoisomer eluted). Fractions containing the pure compounds were combined and freeze dried to afford the title compounds as a white powder (37 %). MS (ES⁺) m/z 498 (M+H)⁺.

Step 6: (5RJSΛ0SΛ2R or SVlO-cvclohexyl^-fmethoxycarbonviy^-methyl-S.g-dioxo- όJ.g.lO.l l.^.n.KlS.lό-decahvdro-lH.SH^^S.δ-dimethano^.δ.l l- benzoxatriazacvcloicosin-11-ium trifluoroacetate 63a (R³=cHex) Zhan catalyst I (0.2 eq.) was added to (3i?,55)-l-{(25)-2-cyclohexyl-2-[((li? and S)- l-methylhept-6- en- 1 -yl)amino]acetyl} -5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinyl- 1 ,3-dihydro-2H-isoindole-2- carboxylate 62 in CH₂Cl₂ (0.02 M) and the mixture was heated under microwave irradiation at 100 ⁰C for 40 min. Volatiles were evaporated under reduced pressure affording a residue, which was redissolved with DMSO and purified by RP-HPLC (stationary phase: column Symmetry C 18, 7 um, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). The title compound 63a was the first diastereoisomer eluted. The fractions containing the pure compounds were combined and freeze dried to afford the title compounds as a white powder (31 %).

63a) ¹H NMR (300 MHz, DMSO-d₆, 300 K) δ 8.60 (br s, 2H), 7.35-7.15 (m, 3H), 6.27 (d, J 16.4, IH,), 6.07 (dt, J 15.8, 5.7, IH), 5.42 (br s, IH), 4.89-4.54 (m, 4H), 4.46 (d, J 14.8, IH), 4.40-4.31 (m, IH), 4.26 (d, J 12.2, IH), 3.76-3.60 (m, 4H), 2.95-2.77 (m, IH), 2.47-2.40 (partially obscured by residual DMSO, IH), 2.30-2.03 (m, 3H), 2.01-1.71 (m, 6H), 1.70-0.97 (m, 14H). MS (ES⁺) m/z 538 (M+H)⁺. Step 7: (5RJSΛ0SΛ2R or ,SyiO-isopropyl-7-(methoxycarbonviyi2-methyl-3.9-dioxo- 6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacycloicosin-11-ium trifluoroacetate 64a (R³ = /Pr)

Palladium on carbon (10% Pd, 20% weight) and (5R,7S,10S,12R or 5^*,17E)-10-isopropyl-7- (methoxycarbonyl)-12-methyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8- dimethano-4,2,8,1 l-benzoxatriazacycloicosin-l 1-ium trifluoroacetate 63a in MeOH (5 mM) were stirred under a hydrogen atmosphere. After 2 h, solids were filtered away on celite and the resulting solution was evaporated under reduced pressure affording the title compound (67%) as a pale brown oil. MS (ES⁺) m/z 500 (M+H)⁺.

Step 7: (5RJSΛ0SΛ2R or .SyiO-cvclohexyl^-fmethoxycarbonviy^-methyl-S^-dioxo- 6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacvcloicosin-11-ium trifluoroacetate 64a (R³ = cHex) Palladium on carbon (10% Pd, 20% weight) and (5R,7S,10S,12R or 5)-10-cyclohexyl-7- (methoxycarbonyl)-12-methyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8- dimethano-4,2,8,1 l-benzoxatriazacycloicosin-l 1-ium trifluoroacetate 63a in methanol (0.013M) were stirred under a hydrogen atmosphere. After 3 h, solids were filtered away on celite and the resulting solution was evaporated under reduced pressure affording the title compound (88%) as a pale brown oil. MS (ES⁺) m/z 540 (M+H)⁺.

Step 8: (5RJSΛ0SΛ2R or ,S)-7-carboxy-10-isopropyl-12-methyl-3.9-dioxo-

6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacvcloicosin-11-ium trifluoroacetate 65a (R³ = /Pr)

Lithium hydroxide monohydrate (12 eq.) was added to a stirred mixture of (5i?,7>S,10>S,12i? or S)-IO- isopropyl-7-(methoxycarbonyl)-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-l//,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosin-l 1-ium trifluoroacetate 64a in MeOH and water (3/1 v/v, 0.01 M) and the mixture was stirred at 40 ⁰C. After 6 h, the mixture was cooled, TFA was added to pH = 1 and the mixture was evaporated under reduced pressure affording a residue, which was redissolved with DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 5 um, 19 x 100 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound 65a as a white powder (57 %). MS (ES⁺) m/z 486 (M+H)⁺.

Step 8: (5RJSΛ0SΛ2R or ^-7-carboxy-10-cvclohexyl-12-methyl-3.9-dioxo- 6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH^'.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacvcloicosin-11-ium trifluoroacetate 65a (R³ = cHex)

Lithium hydroxide monohydrate (5 eq.) was added to a stirred mixture of(5R,7S,10S,12R or S)-IO- cyclohexyl-7-(methoxycarbonyl)-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosin-l 1-ium trifluoroacetate 64a in THF and water (2/1 v/v, 0.01 M) and the mixture was stirred at 40 ⁰C. After 6 h the mixture was cooled, TFA was added to pH = 1 and the mixture was evaporated under reduced pressure affording a residue, which was redissolved with DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 5 urn, 19 x 100 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (44 %). MS (ES⁺) m/z 526 (M+H)⁺.

Step 9: (5RJSΛ0SΛ2R or ^-N-((li?.2^-l-{r(cvclopropylsulfonyl)aminolcarbonvU-2- vinylcvclopropylVlO-isopropyl-^-methyl-S^-dioxo-όJ^.lO.l l.^.n.M.lS.lό.π.lδ- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8J l-benzoxatriazacvcloicosine-7-carboxamide 10 /-Pr₂EtN (7.5 eq.), DMAP (0.5 eq.) and TBTU (1.3 eq.) were added to a stirred mixture of (5R,7S, 105^*, 12R or S)- 10-isopropyl-7-(methoxycarbonyl)- 12-methyl-3 ,9-dioxo- 6,7,9,10,11,12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l- benzoxatriazacycloicosin- 11 -ium trifluoroacetate 65a and (1R,2S)- 1 -

{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride 48 (prepared as described in WO 03/099274) (1.5 eq.) in CH₂Cl₂ (0.02 M) and the mixture was stirred at RT. After 13 h, the mixture was evaporated under reduced pressure affording a residue, which was redissolved with DMSO and purified by RP-HPLC (stationary phase: column Symmetry C18, 7 um, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound 10 (TFA salt) as a white powder (57 %). ¹H NMR (600 MHz, DMSO-d₆, 300 K) δ 10.90 (br s, NH), 8.73 (br s, NH), 8.50-8.25 (m, NH₂), 7.26 (t, J 7.3, IH), 7.18 (d, J 7.4, IH), 7.14 (d, J 7.4, IH), 5.56 (dt, J 17.5, 9.5, IH), 5.41 (br s, IH), 5.22 (d, J 17.5, IH), 5.11 (d, J 11.1, IH), 4.67 (m, 2H), 4.62-4.49 (m, 3H), 4.40-4.34 (m, IH), 4.18 (d, J 12.2, IH), 3.74 (dd, J 12.2, 2.5, IH), 2.94-2.82 (m, 2H), 2.52-2.43 (obscured by residual DMSO, 2H), 2.42-2.34 (m, IH), 2.23 (m, IH), 2.15 (q, J 8.7, IH), 2.06 (m, IH), 1.74 (dd, J 7.6, 5.5, IH), 1.71 (m, IH), 1.63-1.44 (m, 3H), 1.41-0.97 (m, 20H). MS (ES⁺) m/z 698 (M+H)⁺.

Step 9: (5RJSΛ0SΛ2R or ^-10-cvclohexyl-N-((li?.2^-l-{r(cvclopropylsulfonyl)aminolcarbonvU- 2-vinylcvclopropyl)-12-methyl-3.9-dioxo-6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH.5H- 2,22:5, 8-dimethano-4,2, 8, l l-benzoxatriazacvcloicosine-7-carboxamide 25 i-Pr₂EtN (6.5 eq.), DMAP (0.5 eq.) and TBTU (1.3 eq.) were added to a stirred mixture of (5R,7S, 1 OS, 12R or 5)-7-carboxy- 10-cyclohexyl- 12-methyl-3 ,9-dioxo- 6,7,9,10,11,12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l- benzoxatriazacycloicosin- 11 -ium trifluoroacetate 65a and (li?,25)-l-{[(cyclopropylsulfonyl)amino] carbonyl}-2-vinylcyclopropanaminium chloride (prepared as described in WO 03/099274) (1.5 eq.) 48 in CH₂Cl₂ (0.02 M) and the mixture was stirred at RT overnight. Volatiles were evaporated under reduced pressure affording a residue, which was redissolved with DMSO and purified by RP- HPLC (stationary phase: column Symmetry C 18, 7 um, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound 25 (TFA salt) as a white powder (62 %). ¹H NMR (400 MHz, DMSO- d₆, 300 K) δ 10.85 (br s, IH), 8.73 (br s, IH), 8.43 (br s, IH), 8.34-8.20 (m, IH), 7.26 (t, J 7.5, IH,), 7.18 (d, J 7.6, IH), 7.14 (d, J 7.4, IH), 5.58 (dt, J 17.7, 9.1, IH), 5.41 (br s, IH), 5.21 (d, J 17.4, IH), 5.11 (d, J 11.4, IH), 4.72-4.45 (m, 5H), 4.48-4.39 (m, IH), 4.17 (d, J 12.1, IH), 3.76 (dd, J 12.9, 2.3, IH), 2.97-2.78 (m, 2H), 2.47-2.34 (partially obscured by residual DMSO, 2H), 2.19-2.03 (m, 2H), 1.99-1.42 (m, HH), 1.41-0.93 (m, 20H). MS (ES⁺) m/z 738 (M+H)⁺.

Scheme 7

Scheme 8

Compound l9: (5R,7S,10S)-N-((lR,2S)-l-{[(cyclopropylsulfonyl)amino]carbonyl}-2- vinylcyclopropyl)-10-isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15,16,17,18-dodecahydro- lH,5H-2,22:5,8-dimethano-4,2,8,ll-benzoxatriazacycloicosine-7-carboxamide

Step 1: Methyl (2S) -2-(hept-6-en-l-ylamino)-3-methylbutanoate 67 (R³ = /Pr)

To a solution (0.3M) of L-valine, methyl ester, hydrochloride in dry MeOH was added ZnCl2 (1.0 eq.), NaCNBH₃ (1.2 eq.), hept-6-enal 66 (1.2 eq.), and the reaction mixture was stirred at RT overnight. Then the volatiles were evaporated at reduced pressure and the residue taken-up in CH2CI2 and washed with a saturated aq. solution OfNaHCO₃. The organic layer was dried over Na₂SO₄ and evaporated at reduced pressure affording the title compound (98%) as yellow pale oil. ¹H NMR ^OO MHZ, CDCl₃, 300 K) 5 5.81 (ddt, J 17.0, 10.1, 6.7, IH), 5.00 (dd, J 17.0, 1.5, IH), 4.94 (d, J 10.1, IH), 3.72 (s, 3H), 2.99 (d, J 5.6, IH), 2.60-2.54 (m, IH), 2.45-2.39 (m, IH), 2.05 (dd, J 13.5, 6.6, 2H), 1.94-1.86 (m, IH), 1.53-1.26 (m, 6H), 0.96 (d, J 7.1, 3H), 0.93 (d, J 6.8, 3H). Step 2: N-[Q^V l-carboxy-2-methylpropyl1hept-6-en-l -aminium chloride 68 (R³ = /Pr) To a solution (0.4M) of methyl (2S) -2-(hept-6-en-l-ylamino)-3-methylbutanoate 67 in a 1:1 mixture of dioxane and water, LiOH (4 eq.) was added, and the reaction mixture was stirred at reflux for 24h. The reaction mixture was then cooled and brought to pH=2 by small additions of HCl_(aq) 6N. The white precipitate was filtered and washed with H₂O and dried overnight. The title compound (71%) as a white precipitate was used in the next step without any further purification. ¹H NMR (400 MHz, DMSO-d6, 300 K) δ 9.80 (bs, IH), 8.95 (bs, IH), 5.74 (ddt, J 17.0, 16.9, 6.7, IH), 4.95 (d, J 17.0, IH), 4.89 (d, J 10.2, IH), 3.73-3.70 (m, IH), 2.91-2.72 (m, 2H), 2.43-2.35 (m, IH), 1.96 (q, J 6.7, 2H), 1.78-1.65 (m, 2H), 1.33-1.24 (m, 4H), 1.01 (d, J 7.1, 3H), 0.92 (d, J 6.8, 3H).

Step 3 : N- UlS)- 1 -r((2^4i?)-2-(methoxycarbonyl)-4- (IY4-vinyl- 1.3-dihydro-2H-isoindol-2- vDcarbonylloxylpyrrolidin- 1 -yl)carbonyll-2-methylpropyUhept-6-en- 1 -aminium trifluoroacetate 69 (R³ = /Pr) To a solution (0.1M) of N-[(15)-l-carboxy-2-methylpropyl]hept-6-en-l-aminium chloride 68 in dry CH₂Cl₂ was added (25^*,4i?)-2-(methoxycarbonyl)-4-{[(4-vinyl-l,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}pyrrolidinium chloride 43 (1.2 eq.), z^'-Pr₂Et(3.2 eq.) and TBTU (1.2 eq.). The reaction mixture was stirred at RT for 4h, then taken up in DCM and washed with an aq. saturated solution of NaHCOs. The organic phase was dried over Na₂SO₄ and the volatiles evaporated at reduced pressure. The crude was purified by flash chromatography eluting with a mixture of

PE/EtOAc (7/3) in presence with 0.1% of TEA. The desired fractions were collected and the solvent evaporated. The compound was solubilized in CH₂Cl₂ and 1 eq. of TFA was added in order to obtain the complete formation of the trifluoroacetate salt. The procedure afforded the title compound (90%) as a white solid. MS (ES⁺) m/z 512 (M+H)⁺.

Step 4: N-(5RJS, 1 OS.1 IE)- 10-isopropyl-7-(methoxycarbonyl)-3.9-dioxo-

6.7.9.10.11.12.13.14.15.16-decahydro-lH.5H-2.22:5.8-dimethano-4.2.8.11- benzoxatriazacvcloicosin-11-ium trifluoroacetate 70 (R³ = /Pr)

Zhan catalyst I (0.05 eq.) was added to N-{(15)-l-[((25^*,4i?)-2-(methoxycarbonyl)-4-{[(4-vinyl-l,3- dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidin- 1 -yl)carbonyl]-2-methylpropyl}hept-6-en- 1 - aminium trifluoroacetate 69 in DCE (0.04 M) and the mixture was heated at 90⁰C for Ih. The volatiles were then evaporated at reduced pressure and the crude crystallized from a mixture of PE/EtOAc 8/2. The precipitate was collected and dried overnight. The title compound (78%) was obtained as a brownish solid. MS (ES⁺) m/z 484 (M+H)⁺.

Step Si fS^JS.lO^-lO-isopropyl^-fmethoxycarbonylVS^-dioxo-όJ^.lO.l l.^.n.M.lS.lό.π.lδ- dodecahvdro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacvcloicosin-l 1-ium trifluoroacetate 71 (R³ = /Pr) Palladium on carbon (10% Pd, 20% weight) and N-(5R JS, 1OS, 17E)-10-isopropyl-7- (methoxycarbonyl)-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8-dimethano- 4,2,8,11-benzoxatriazacycloicosin-l 1-ium trifluoroacetate 70 in MeOH (1 mM) were stirred overnight under hydrogen atmosphere. Then the catalyst was filtered-ofTand the volatiles evaporated. The title compound (95%) was recovered as a brown solid. MS (ES⁺) m/z 487 (M+H)⁺.

Step 6: (5i?.7S.10,Sy7-carboxy-10-isopropyl-3.9-dioxo-6.7.9.10.11.12.13.14.15.16.17.18- dodecahvdro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacvcloicosin-l 1-ium trifluoroacetate 72 (R³ = /Pr) Lithium hydroxide monohydrate (5 eq.) was added to a stirred mixture of (5i?,75^*,105)-10-isopropyl- 7-(methoxycarbonyl)-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8- dimethano-4,2,8,11-benzoxatriazacycloicosin-l 1-ium trifluoroacetate 71 in a 1:1 mixture of dioxane and H₂O (3 mM). By small aliquots of HCl_(aq) 6N the pH was brought to 6.5 and the volatiles evaporated. The crude was taken up in a mixture 95:5 H₂O:MeCN and the solid was collected by suction. The title compound (quantitative recovery) was obtained as a light grey solid. MS (ES⁺) m/z All (M+H)⁺.

Step 7: (5RJS.1 OS)-N-(C 1R.2SV 1 - ( rCcvclopropylsulfonyPaminolcarbonyli -2-vinylcvclopropyl)- 10- isopropyl-3.9-dioxo-6.7.9.10.11.12.13.14.15.16.17.18-dodecahvdro-lH.5H-2.22:5.8-dimethano- 4,2,8,1 l-benzoxatriazacvcloicosine-7-carboxamide 19

/-Pr₂EtN (3.5 eq.), DMAP (0.5 eq.), TBTU (1.5 eq.) were added to a stirred mixture Of (SRJS₉IO-S)- 7-carboxy-10-isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8- dimethano-4,2,8,11-benzoxatriazacycloicosin-l 1-ium trifluoroacetate 72 and (1R,2S)-1- {[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride (prepared as described in WO 03/099274) (1.5 eq.) 48 (1.5 eq.) in CH₂Cl₂ (0.06 M) and the mixture was stirred at RT for 2 h. The mixture was evaporated under reduced pressure affording a residue, which was redissolved with DMSO and purified by RP-HPLC (stationary phase: column Symmetry C 18, 7 um, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound 19 (TFA salt) as a white solid (23%). ¹H NMR (400 MHz, DMSO-d6, 300 K) δ 10.74 (s, IH), 8.74 (s, IH), 8.70-8.56 (m, 2H), 7.25 (t, J 7.6, IH), 7.17 (d, J 7.8, IH), 7.13 (d, J 7.3, IH), 5.56 (dt, J 17.1, 9.3, IH), 5.39 (br s, IH), 5.22 (d, J 17.4, IH), 5.11 (d, J 11.3, IH), 4.78-4.48 (m, 5H), 4.27 (br s, IH), 3.74 (dd, J 11.6, 2.5, IH), 2.95- 2.89 (m, 2H), 2.69-2.66 (m, IH), 2.38-2.32 (obscured by residual DMSO, IH), 2.21-2.06(m, 3H), 1.73 (dd, J 9.7, 6.9, 2H), 1.69-1.55 (m, 4H), 1.32-1.26 (m, IH), 4.49-4.62 (m, 7H), 1.15-1.09 (m, IH), 1.04 (dd, J 9.7, 6.9, 9H). MS (ES⁺) m/z 685 (M⁺H)⁺.

Scheme 9

Compound 26: (5R,7S,10S,12R or S)-10-cyclohexyl-N-((lR,2S)-l- {[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-ll,12-dimethyl-3,9-dioxo- 6,7,9,10,ll,12,13,14,15,16,17,18-dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,ll- benzoxatriazacycloicosine-7-carboxamide

A solution of NaCNBH₃ (1.2 eq.) and ZnCl₂ (0.6 eq.) in methanol (0.04 M with respect to

NaCNBH₃) was added dropwise to a solution of 37% aq. formaldehyde (35 eq.) and

(5R,7S, 1 OS, 12R or S)- 10-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18-dodecahydro-lH,5H- 2,22:5, 8-dimethano-4,2, 8, l l-benzoxatriazacycloicosine-7-carboxamide 25 in MeOH (0.03 M). After stirring overnight, volatiles were evaporated under reduced pressure. The residue was redissolved with DMSO and purified by RP-HPLC (stationary phase: column Symmetry Cl 8, 7 um, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound 26 (TFA salt) as a white powder (55 %). ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 10.88 (s, IH), 8.73 (br s, IH), 8.65 (br s, IH), 7.26 (t, J 7.5, IH), 7.19 (d, J 7.6, IH), 7.13 (d, J 7.4, IH), 5.60 (dt, J 17.3, 9.5, IH), 5.37 (br s, IH), 5.20 (d, J 17.0, IH), 5.11 (d, J 11.1, IH), 4.77-5.55 (m, 4H), 4.56-4.39 (m, 2H), 3.92 (d, J 12.1, IH), 3.80 (dd, J 12.1, 2.5, IH), 2.97-2.80 (m, 2H), 2.62 (d, J 4.0, 3H), 2.47- 2.36 (partially obscured by residual DMSO, 3H), 2.15 (q, J 8.9, IH), 2.10-1.93 (m, 2H), 1.92- 1.41 (m, 12H), 1.40-1.81 (m, HH), 1.17-0.94 (m, 6H). MS (ES⁺) m/z 752 (M+H)⁺.

Scheme 10

Compound 14: (5R,7S,10S)-N-((lR,2S)-l-{[(cyclopropylsulfonyl)amino]carbonyl}-2- vinylcyclopropyl)-13,13-difluoro-10-isopropyl-3,9-dioxo-6,7,9,10,ll, 12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,ll-benzoxatriazacycloicosine-7-carboxamide

Step 1: methyl N-(2.2-difluorohept-6-en-l-yl)-L-valinate 73

To hept-6-enal 59 dissolved in TΗF (0.09M), racemic proline, followed by N-Αworo-N- (phenylsulfonyl)benzenesulfonamide were added. The mixture was stirred at RT overnight. The reaction mixture was diluted with Et₂O and washed with sat. aq. NaΗCC>3 The organic layer was separated, dried over Na₂SO₄, filtered and concentrated. To the residue redissolved in MeOH (0.5 M), L-valine methyl ester hydrochloride (1.1 eq.) followed by a solution OfNaCNBH₃ (1.2 eq.) and ZnCl₂ (0.6 eq.) in MeOH (0.3 M with respect to NaCNBH₃) were added dropwise. After stirring overnight, volatiles were evaporated under reduced pressure and the residue partitioned between CH₂Cl₂ and sat. aq. NaHCO₃. The organic layer was dried (Na₂SO₄) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:PE = 5:95) to afford the title compound as a yellow oil (25%). ¹H NMR (400 MHz, DMSOd₆, 300 K) δ 5.86 (m, IH), 5.03 (d, J 17.2, IH), 5.0 (d, J 10.1, IH), 3.65 (s, 3H), 3.05- 2.87 (m, 2H), 2.76-2.60 (m, IH), 2.25-2.15 (m, IH), 2.13-1.99 (m, 2H), 1.97-1.77 (m, 3H), 1.56-1.40 (m, 2H), 0.86 (d, J 6.8, 6H). MS (ES⁺) m/z 264 (M+H)⁺.

Step 2: N-(2.2-difluorohept-6-en-l-yl)-L-valine 74

Lithium hydroxide monohydrate (6 eq.) was added to a stirred mixture of methyl N-(2,2- difiuorohept-6-en-l-yl)-L-valinate 73 in THF and water (2/1 v/v, 0.013 M) and the mixture was stirred at 60⁰C. After 1 h, it was cooled to RT and THF was evaporated under reduced pressure.

Aqueous IN HCl was added until pH = 5, and the aq. phase was extracted with EtOAc. Drying over Na₂SO₄, filtration and evaporation under reduced pressure afforded the title compound that was used in the following step without further purification. MS (ES⁺) m/z 250 (M+H)⁺.

Step 3 : methyl N-(2.2-difluorohept-6-en- 1 -yl)-L-valyl-(4i?)-4- ( IY4-vinyl- 1.3-dihydro-2H-isoindol-2- vDcarbonylloxyl-L-prolinate 75

/-Pr₂EtN (2.2 eq.) followed by TBTU (1.2 eq.) was added to a stirred mixture of N-(2,2- difiuorohept-6-en-l-yl)-L-valine 74 and (25^*,4i?)-2-(methoxycarbonyl)-4-{[(4-vinyl-l,3-dihydro-2H- isoindol-2-yl)carbonyl]oxy}pyrrolidinium chloride (1 eq.) in CH₂Cl₂ (0.06 M) and the mixture was stirred at RT overnight. Sat. aq. NaHCOs was added, the organic layer was separated and dried (Na₂SO₄). Evaporation under reduced pressure afforded a residue, which was purified by flash chromatography on silica gel (EtOAc:PE = 1 :9). The title compound was obtained as a yellow foam (39%). MS (ES⁺) m/z 548 (M+H)⁺.

Step 4: Methyl (5i?.7^10^17Z)-13.13-difluoro-10-isopropyl-3.9-dioxo-6.7.9.10.11.12.13.14.15.16- decahvdro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacvcloicosine-7-carboxylate 76 Zhan catalyst I (0.2 eq.) was added to methyl N-(2,2-difiuorohept-6-en-l-yl)-L-valyl-(4i?)-4-{ [(4- vinyl-l,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate 75 in CH₂Cl₂ (0.02 M) and the mixture was heated under microwave irradiation at 100 ⁰C for 15 min. Volatiles were evaporated under reduced pressure affording a residue, which was purified by flash chromatography on silica gel (EtOAc:PE = 2:8). The title compound was obtained as a yellow foam (66%). MS (ES⁺) m/z 520 (M+H)⁺.

Step 5: methvK5i?.7S.10,Syi3.13-difluoro-10-isopropyl-3.9-dioxo- 6.7.9.10.11.12.13.14.15. lό.π.lδ-dodecahvdro-lH.SH^^^.δ-dimethano^^.δ.l l- benzoxatriazacvcloicosine-7-carboxylate 77

Palladium on carbon (10% Pd, 20% weight) and methyl (S^J^lO^πz^-DJS-difiuoro-lO- isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l- benzoxatriazacycloicosine-7-carboxylate 76 in MeOH (0.02M) were stirred under a hydrogen atmosphere. After 4 h solids were filtered on celite and the resulting solution was evaporated under reduced pressure affording the title compound as a pale brown oil. MS (ES⁺) m/z 522 (M+H)⁺.

Step 6: (5i?.7^10^-13.13-difluoro-10-isopropyl-3.9-dioxo-6.7.9.10.11.12.13.14.15.16.17.18- dodecahvdro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacvcloicosine-7-carboxylic acid 79 Lithium hydroxide monohydrate (3 eq.) was added to a stirred mixture of methyl (5i?,75^*,105)-13,13- difiuoro-10-isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8- dimethano-4,2,8,1 l-benzoxatriazacycloicosine-7-carboxylate 77 in THF and water (2/1 v/v, 0.02 M) and the mixture was stirred at RT overnight. Aqueous HCl (IN) was added to reach pH = 5 and the mixture was extracted with EtOAc. The organic layer was separated, dried over Na₂SO₄, filtered and concentrated to obtain the crude product which was used in the following step without further purification. MS (ES⁺) m/z 508 (M+H)⁺.

Step 7: (5RJS, 1 OS)-N-((1R,2S)- 1 - ( [(cvclopropylsulfonvBaminolcarbonyli -2-vinylcvclopropyl)- 13.13-difluoro-10-isopropyl-3.9-dioxo-6.7.9.10.11.12.13.14.15.16.17.18-dodecahydro-lH.5H- 2,22:5, 8-dimethano-4,2, 8, l l-benzoxatriazacvcloicosine-7-carboxamide 14 /-Pr₂EtN (6.5 eq.), DMAP (0.5 eq.) and TBTU (1.3 eq.) were added to a stirred mixture of (5i?,75,105)-13,13-difluoro-10-isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro- lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxylic acid 78 and (IR,2S)-1- {[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride (prepared as described in WO 03/099274) (1.5 eq.) 48 (1.5 eq.) in CH₂Cl₂ (0.02 M) and the mixture was stirred at RT. After 13 h, the mixture was evaporated under reduced pressure affording a residue, which was redissolved in DMSO and purified by RP-HPLC (stationary phase: column Symmetry C 18, 7 um, 19 x 300 mm. Mobile phase: MeCN/H₂O buffered with 0.1 % TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound 14 as a white powder (15 % over three steps). ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 10.66 (s, IH), 8.97 (br s, IH), 7.25 (t, J 7.5, IH), 7.17 (d, J 7.3, IH), 7.13 (d, J 7.6, IH), 5.61 (dt, J 17.3, 9.5, IH), 5.38 (br s, IH), 5.25 (d, J 16.9, IH), 5.11 (d, J 11.4, IH), 4.73-4.54 (m, 4H), 4.45 (dd, J 10.1, 7.3, IH), 4.04 (d, J 12.1, IH), 3.75 (dd, J 12.0, 3.2, IH), 3.50-3.02 (m, 3H), 2.96-2.85 (m, IH), 2.45-2.34 (partially obscured by residual DMSO, 3H), 2.24-1.67 (m, 6H), 1.66-1.48 (m, 2H), 1.49-1.20 (m, 5H), 1.14-0.91 (m, 10H). MS (ES⁺) m/z 720 (M+H)⁺.

Scheme 11

Compound 43: (3R,55)-5-(methoxycarbonyl)pyrrolidin-3-yl-4-vinyl-l,3-dihydro-2H- isoindole-2-carboxylate hydrochloride

Step 1: l-bromo-2,3-bis(bromomethyl)benzene 80

A suspension of 3-bromo-ø-xylene (1.0 eq.), 7V-bromosuccinimide (2.15 eq.) and benzoyl peroxide (1.0 eq.) in CCl₄ (0.55 M) was heated to reflux under nitrogen for 15 h. The contents of the reaction flask were cooled, filtered, and the filtrate evaporated. The crude material was distilled under high vacuum. Major fractions were distilled between 88 ⁰C and 152 ⁰C. Pure material was recovered in 85% yield. ¹H NMR (CDCl₃) δ (ppm) 7.56 (d, J 8.0, IH), 7.31 (d, J 8.0, IH), 7.26 (s, IH), 7.16 (t, J 8.0, IH), 4.84 (s, 2H), 4.64 (s, 2H).

Step 2: 2-benzyl-4-bromoisoindoline 81 Potassium bicarbonate (2.5 eq.) was suspended in MeCN (0.17 M) and the mixture was heated to 80 ⁰C. Solutions of l-bromo-2,3-bis(bromomethyl)benzene 80 (1.0 eq.) in MeCN (1.64 M) and benzylamine (1.0 eq.) in MeCN (1.64 M) were added concurrently via addition funnels over 1 h. The reaction mixture was stirred at 77 ⁰C for 16h. The contents of the reaction flask were cooled, filtered and the solvent removed by evaporation. The reaction was partitioned between IM K₂CO₃ and EtOAc. The organics were washed with brine, dried with anhydrous Na₂SO₄, filtered, and evaporated. Flash column chromatography (gradient elution: heptane to 10% EtOAc in heptane) gave after evaporation the title compound 81 as a pale oil. ¹H NMR (CDCI3) δ (ppm) 7.41-7.39 (m, 2H), 7.37-7.34 (m, 2H), 7.32-7.27 (m, 2H), 7.10-7.03 (m, 2H), 4.02 (s, 2H), 3.97 (s, 2H), 3.91 (s, 2H). LRMS (ESI) m/z 289 (M+H)⁺. Converted to HCl salt in HCl/MeOH by adding MTBE and filtering solid to give the corresponding HCl salt. Step 3: 2-benzyl-4-vinylisoindoline 82

A solution of 2-benzyl-4-bromoisoindoline 81 (1.0 eq.) and tributyl(vinyl)tin (1.2 eq.) in toluene (4 M) was degassed by bubbling nitrogen gas through the solution for 0.25h. Tetrakis(triphenylphosphine)palladium(0) (0.02 eq.) was added and the resulting solution heated in a 100 ⁰C oil bath under nitrogen for 24h. The contents of the reaction flask were cooled, evaporated and subjected to flash column chromatography eluting with hexane/EtOAc 95/5 to give after evaporation the title compound as a pale oil that turned pink on standing. LRMS (ESI) m/z 236 (M+H)⁺.

Step 4: 4-vinylisoindoline 83

A solution of 2-benzyl-4-vinylisoindoline 82 (1.0 eq.) in DCE (0.38 M) was placed in a round bottom flask under nitrogen. To this was attached an addition funnel containing a solution of 1- chloroethyl chloro formate (1.2 eq.) in DCE. The reaction flask was cooled in an ice bath and the contents of the addition funnel were added dropwise over 20 min keeping the internal reaction temperature <5 ⁰C. After the addition was complete the reaction flask was allowed to warm to RT then heated to reflux for 45 min. The contents of the reaction flask were cooled to RT then the solvent removed by evaporation. MeOH was added and the contents of the reaction flask were heated to reflux for 30 min. The reaction flask was cooled and the solvent removed by evaporation. Water was added and the resulting mixture washed with EtOAc. The aqueous layer was made basic with 2N sodium hydroxide then extracted with DCM (4x250 mL). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and the filtrate evaporated. The remaining residue was subjected to flash column chromatography eluting with DCM/MeOH/ammonium hydroxide 97/3/0.3 to 95/5/0.5. Evaporation of fractions gave the title compound 83 as a brown oil, (71% for two steps). LRMS (ESI) m/z 146 (M+H)⁺.

Step 5: 1-tert-butyl 2-methyl (26'.4i?)-4-(r(4-vinyl-1.3-dihvdro-2H-isoindol-2- vDcarbonylloxylpyrrolidine- 1 ,2-dicarboxylate 84

A solution of 1-tøt-butyl 2-methyl (25^*,4i?)-4-hydroxypyrrolidine-l,2-dicarboxylate (1.0 eq.) in DMF (0.5 M) under nitrogen was cooled to 0 ⁰C. Solid l,l'-carbonyldiimidazole (1.0 eq.) was added to the reaction. The contents of the reaction flask were warmed to RT and after 2 h a solution of 4-vinylisoindoline (1.0 eq.) in DMF (4 M) was added. The reaction was heated in a 60 ⁰C oil bath for 2 h then cooled and poured into water and 5% potassium bisulfate. The resulting mixture was extracted with EtOAc. Combined organics were washed with brine, dried with anhydrous sodium sulfate, filtered and evaporated. Flash column chromatography eluting with hexane/EtOAc 70/30 gave the title compound as a white foam (81%). LRMS (ESI) m/z 417 (M+H).

Scheme 12

Compound 50: (2S,4R)-2-(methoxycarbonyl)-4-[(7-vinylisoquinolin-l-yl)oxy]pyrrolidinium chloride

Step 1: l-tert-butyl 2-methyl (26^*,4i?)-4-r(7-bromoisoquinolin-l-yl)oxylpyrrolidine-l,2- dicarboxylate 85

To a solution of trans 4-hydroxy L-BOC-proline (1 eq) in DMSO (0.2 M) at RT was added 'BuOK (3 eq) in a single portion. The reaction mixture was stirred at RT for 30 min, cooled to 10⁰C and 7-bromo-l-chloroisoquinoline was added (1 eq). The resulting mixture was allowed to warm to RT and stirred overnight. The organic layer was washed with citric acid 10% solution, water and brine and the aqueous phases were back extracted with EtOAc. The combined organic phases were dried (Na₂SO₄) and the solvent evaporated under reduced pressure to give a dark solid that was dissolved in MeOH. To the stirred solution, trimethylsilyldiazomethane 2.0 M in hexanes (4.0 eq.) was added dropwise at 15 ⁰C. The resulting mixture was stirred for 15 min after gas evolution has ceased. Volatiles were removed by rotary evaporation and the residue was purified by flash chromatography (Horizon system, column SiO₂, eluent: PEiEtOAc with EtOAc (from 60 to 80%) to give the title product 85 as a solid (71%). MS (ES⁺) m/z 452 (M+H⁺).

Step 2: \-tert-butγl 2-methyl (26^*,4i?)-4-r(7-vinylisoquinolin-l-yl)oxylpyrrolidine-l,2- dicarboxylate 86

Aryl bromide 85 (1.0 eq.) was dissolved in toluene (0.2 M) and treated with tributylvinyltin (1.5 eq) and [Ph₃P]₄Pd(O) (0.1 eq). The reaction mixture was stirred at 80⁰C under N₂ atmosphere for 2 h. After cooling to RT, the reaction mixture was poured into EtOAc and washed with brine. The organic phase was separated, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash chromatography (Horizon system, column SiO₂, eluent: PEiEtOAc with EtOAc from 20 to 40%) to give the title compound 86 as a viscous oil (74%). MS (ES⁺) m/z 399 (M+H⁺). Step 3: (26^*,4i?)-2-(methoxycarbonyl)-4-r(7-vinylisoquinolin-l-yl)oxylpyrrolidinium chloride 50 Carbamate 86 was dissolved in a 4.0 M HCl solution in dioxane. The resulting mixture was stirred at RT for 0.5 h, during which time the product precipitated. The title compound 50 was filtered off and washed with hexane/EtOAc 1/1 v/v (96%). ¹H NMR (400 MHz, DMSOd₆, 300 K) δ 8.30 (s, IH), 8.01-7.98 (m, 2H), 7.89 (d, J 8.5, IH), 7.43 (d, J 5.8, IH), 6.93 (dd, J 17.6, 10.9, IH), 6.07 (d, J 17.6, IH), 5.85 (bs, IH), 5.43 (d, J 11.0, IH), 4.86 (dd, J 10.4, 7.7, IH), 3.81 (s, 3H), 3.78-3.74 (m, IH), 3.60 (d, J 12.8, IH), 2.71-2.66 (m, IH), 2.57-2.50 (m, partially obscured by residual DMSO, IH). MS (ES⁺) m/z 299 (M+H⁺).

Scheme 13

Compound 49: (lR,25)-l-amino-N-(cyclopropylsulfonyl)amino-2-ethylcyclopropane carboxamide hydrochloride

Step 1: ferf -butyl ((li?,2i?)-l-{r(cvclopropylsulfonyl)aminolcarbonvU-2- ethylcvclopropyDcarbamate 88

A hydrogenation vessel was charged with a solution of tøt-butyl ((1R,2S)-1- {[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)carbamate 87 (prepared as described in WO 03/099274) in MeOH followed by Ru/C (7.5 wt%). The vessel was placed under N₂ (20 psig) and vented to atmospheric pressure three times to remove residual oxygen. The vessel was then placed under H₂ (50 psig) and the reaction was complete in <5 h based on H₂ consumption. After 20 h, the vessel was vented to atmospheric pressure. The reaction slurry was then filtered and evaporated to a yellow oil which was brought to the following step without further purification. MS (ES⁺) m/z 333 (M+H⁺).

Step 2: (li?,26^f)-l-amino-Λ/-(cvclopropylsulfonyl)amino-2-ethylcvclopropane carboxamide hydrochloride 49

A 0.33 M solution of carbamate in 4N HCl/dioxane was stirred at RT for 12 h. The volatiles were then removed under reduced pressure to give the title compound 49 as a pale yellow solid that was used directly in the next step. ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (bs, 2H), 3.03 (m, IH), 1.71-1.37 (m, 5H), 1.16-1.09 (m, 4H), 0.97 (t, J 7.3, 3H).

Scheme 14

Scheme 15

Scheme 16

Compound 142: (9R,11S,14S)-14-tert-butyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-13-oxo-8-oxa-12,15- diazatetracyclo[20.3.1.1²'⁶.1^{9 12}]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxamide Step 1: (3'-bromobiphenyl-3-yl)methanol 94

To a 0.2 M solution of [3-(hydroxymethyl)phenyl]boronic acid in DME were sequentially added 1- bromo-3-iodobenzene (0.83 eq.) and a 2M solution of Na₂COs (3.0 eq.). The reaction mixture was degassed, trans-bis(triphenylphosphine)palladium(II) chloride (0.01 eq.) was added and it was stirred at 80⁰C for 6h. After cooling down to RT the reaction mixture was diluted with EtOAc and washed with saturated aq. NaHCOs, IN HCl and brine. The residue was dried (Na₂SO₄) and evaporated under reduced pressure to afford an oil which was purified by flash chromatography (SiO₂, PE:EtOAc=8:2) to afford the title compound 94 as an oil (80%). ¹H NMR (400 MHz, DMSO-de, 300 K) δ 7.87 (s, IH), 7.71 (d, J 7.7, IH), 7.66 (bs, IH), 7.59 (t, J 6.8, 2H), 7.47 (t, J 7.7, 2H), 7.39 (d, J 7.7, IH), 4.61 (s, 2H).

Step 2: 3-bromo-3'-(bromomethyl)biphenyl 95

A 0.5 M solution of (3'-bromobiphenyl-3-yl)methanol 94 in DCM was added to a 10 min. prestirred suspension of triphenylphosphine resin (1.6 eq.), Br₂ (1.6 eq.) and 0.25 M solution of imidazole (1.7 eq.) in DCM. The reaction mixture was gently stirred at RT for 3h. The resin was then filtered off and washed with DCM, the filtrate was evaporated to dryness to afford the title compound 95 (78% crude yield) as a brown oil. The material was used in the following step without further purification. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 7.90 (s, IH), 7.86-7.82 (m, IH), 7.76-7.70 (m, IH), 7.70-7.65 (m, IH), 7.65-7.60 (m, IH), 7.55-7.49 (m, 2H), 7.47 (d, J 7.8, IH), 4.81 (s, 2H).

Step 3: 1-ferf -butyl 2 -methyl (26',4i?)-4-r(3'-bromobiphenyl-3-yl)methoxylpyrrolidine-l,2- dicarboxylate 96

(4i?)-l-(tert-butoxycarbonyl)-4-hydroxy-L-proline (1.0 eq.) in DMF was added to a 0⁰C cooled suspension of 18-crown-6 (0.1 eq.) and NaH (3.0 eq.) in DMF (0.5 M final concentration). The reaction mixture was allowed to warm up to RT and stirred for 1 h. A 0.5M solution of 3-bromo- 3'-(bromomethyl)biphenyl 95 (1.0 eq.) in DMF was added dropwise and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with aqueous HCl (IN) at 0⁰C and diluted with EtOAc. The organic layer was separated, washed with aqueous HCl (IN) and brine, dried (Na₂SO₄) and evaporated to a solid. MS (ES⁺) m/z 498, 500 (M+Na)⁺. A 0.5 M solution of the crude material in a mixture of toluene:MeOH (2:1) was cooled to 0⁰C and treated dropwise with TMS-diazomethane (1.5 eq.). The reaction mixture was allowed to warm up to RT and stirred for 1 h. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography (SiO₂, PE:EtOAc=8:2) to afford the title compound 96 as a yellow oil (78%). ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 7.90-7.86 (m, IH), 7.71 (d, J 7.7, IH), 7.69-7.58 (m, 3H), 7.54-7.44 (m, 2H), 7.40 (d, J 7.7, IH), 4.66-4.55 (m, 2H), 4.31-4.21 (m, 2H), 3.74-3.65 (m, 3H), 3.60-3.45 (m, 2H), 2.51-2.37 (m, IH), 2.10-2.00 (m, IH), 1.44-1.31 (m, 9H). MS (ES⁺) m/z 512, 514 (M+Na)⁺. Step 4: (26^*,4i?)-4-r(3'-bromobiphenyl-3-yl)methoxyl-2-(methoxycarbonyl)pyrrolidinium chloride 97 1-tert-Butyl 2-methyl (25^*,4i?)-4-[(3'-bromobiphenyl-3-yl)methoxy]pyrrolidine-l,2-dicarboxylate 96 (1.0 eq.) was dissolved at 0⁰C in a 4M solution of HCl in dioxane (3.0 eq.) to give a 1.0 M solution. The reaction mixture was stirred at RT for 2h then the solvent was evaporated under reduced pressure to afford the title compound 97 as a white foam (96%). ¹H NMR (400 MHz, DMSOd₆, 300 K) δ 10.33-9.33 (bs, IH), 7.89 (s, IH), 7.77-7.71 (m, 2H), 7.67 (d, J 7.7, IH), 7.62 (d, J 7.7, IH), 7.54-7.43 (m, 3H), 4.63 (s, 2H), 4.55 (dd, J 10.7, 7.4 Hz, IH), 4.41 (bs, IH), 3.81 (s, 3H), 3.51-3.40 (m, 2H), 2.59-2.51 (m, IH), 2.27-2.16 (m, IH). MS (ES⁺) m/z 390, 392 (M+H)⁺.

Step 5: methyl iV-hex-5 -en- l-yl-3-methyl-L-valinate 99

Hex-5-enal 98 (obtained from hex-5-en-l-ol via a PCC oxidation) (0.95 eq.) was added at RT to a 0.11 M solution of (25)-l-methoxy-3,3-dimethyl-l-oxobutan-2-aminium chloride (1.0 eq.) and TEA (1.0 eq.) in DCE. Sodium triacetoxyborohydride (1.0 eq.) was added in one portion and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM/saturated aqueous NaHCC>3. The phases were separated; the organic layer was washed with brine, dried (Na₂SO₄) and filtered though a short path of silica gel (PE:EtOAc=9:l) to afford the title compound 99 as a pale yellow liquid (72 %). ¹H NMR (300 MHz, CDCl₃, 300 K) δ 5.89-5.71 (m, IH), 5.07-4.88 (m, 2H), 3.71 (s, 3H), 2.88 (s, IH), 2.62-2.48 (m, IH), 2.45-2.31 (m, IH), 2.13-1.98 (m, 2H), 1.67-1.54 (m, IH), 1.53-1.35 (m, 4H), 0.95 (s, 9H).

Step 6: Λ/-hex-5-en-l-yl-3-methyl-L-valine 100

A 0.25M solution of methyl TV-hex- 5 -en- l-yl-3-methyl-L-valinate 99 in a mixture of MeOH:water (3:1) was treated with LiOH (3.0 eq.) at RT. The reaction mixture was stirred at 70⁰C for 3h. The organic solvent was removed under reduced pressure and the residue was acidified with aqueous HCl (IN). The water phase was repeatedly extracted with EtOAc, dried (Na₂SO₄) and concentrated under reduced pressure to afford the crude product, which was used in the following step without further purification. MS (ES⁺) m/z 214 (M+H)⁺

Step 7 : methyl iV-hex-5 -en- 1 -yl-3 -methyl-L-valyl-(4i?)-4- [(3 '-bromobiphenyl-3 -vDmethoxyl -L- prolinate 101

7V-hex-5-en-l-yl-3-methyl-L-valine (1.2 eq.), DIPEA (3.7 eq.) and HATU (1.2 eq.) were sequentially added to a 0.10 M solution of (25^*, 4R)-4- [(3 '-bromobiphenyl-3 -yl)methoxy] -2- (methoxycarbonyl)pyrrolidinium chloride in DMF. The reaction mixture was stirred at RT overnight then it was diluted with H₂O/EtOAc and extracted. The collected organic layers were washed with brine, dried (Na₂SO₄) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO₂, PEiEtOAc with EtOAc from 30 to 100%) to afford the title compound 101 as a solid (50%). ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 7.85 (bs, IH), 7.69 (d, J 7.8, IH), 7.66-7.58 (m, 3H), 7.51-7.43 (m, 2H), 7.37 (d, J 7.8, IH), 5.76-5.64 (m, IH), 4.97- 4.87 (m, 2H), 4.63 (s, 2H), 4.45 (t, J 8.6, IH), 4.31 (bs, IH), 4.07 (d, J 11.7, IH), 3.66 (s, 3H), 3.73-3.55 (m, 2H), 2.50-2.41 (m, IH), 2.40-2.32 (m, IH), 2.31-2.23 (m, IH), 2.08-1.96 (m, IH), 1.94-1.85 (m, 2H), 1.34-1.18 (m, 3H), 0.96 (s, 9H), 0.94-0.85 (m, 2H). MS (ES⁺) m/z 585, 587 (M+H)⁺.

Step 8: methyl Λ/-hex-5-en-l-yl-3-methyl-L-valyl-(4i?)-4-r(3'-vinylbiphenyl-3-yl)methoxyl-L- prolinate 102

Vinyltri-n-butyltin (1.5 eq.) was added to a 0.08 M degassed solution of methyl 7V-hex-5-en-l-yl-3- methyl-L-valyl-(4i?)-4-[(3'-bromobiphenyl-3-yl)methoxy]-L-prolinate 101 in toluene. Tetrakis (triphenylphosphine) palladium(O) (0.15 eq.) was added and the reaction mixture was stirred in a preheated oil bath (100⁰C) for 2h. The crude mixture was cooled down to RT and evaporated under reduced pressure to give a residue that was purified by flash chromatography (SiO₂, PE:EtOAc=7:3) to afford the title compound 102 as a yellow oil (38 %). ¹H NMR (400 MHz, DMSOd₆, 300K) δ 7.74 (bs, IH), 7.69-7.60 (m, 2H), 7.57 (d, J 7.7, IH), 7.52 (t, J 7.7, IH), 7.50- 7.44 (m, 2H), 7.34 (d, J 7.7, IH), 6.86 (dd, J 17.7, 10.9, IH), 5.97 (d, J 17.7, IH), 5.76-5.64 (m, IH), 5.36 (d, J 10.9, IH), 4.97-4.86 (m, 2H), 4.63 (s, 2H), 4.46 (t, J 8.6, IH), 4.31 (bs, IH), 3.74- 3.55 (m, 2H), 3.66 (s, 3H), 2.50-2.41 (m, IH), 2.40-2.31 (m, IH), 2.31-2.23 (m, IH), 1.94-1.85 (m, 2H), 1.70-1.53 (m, 3H), 1.41-1.30 (m, 4H), 1.00-0.85 (m, 8H), 0.96 (s, 9H). MS (ES⁺) m/z 533 (M+H)⁺

Step 9: Methyl (9RΛ lSΛ4S20E)-\4-tert-butγl-\3-oxo-S-oxa-\2Λ5- diazatetracvclor20.3.1.1²'⁶.l⁹'¹²loctacosa-l(26).2(28).3.5.20.22.24-heptaene-l l-carboxylate l03 Zhan catalyst I (0.15 eq.) was added to a 0.01 M solution of methyl 7V-hex-5-en-l-yl-3-methyl-L- valyl-(4i?)-4-[(3'-vinylbiphenyl-3-yl)methoxy]-L-prolinate 102 in DCM containing trifiuoroacetic acid (1.3 eq.). The reaction mixture was stirred under microwave irradiation at 100⁰C for 20 min. The crude material was evaporated under reduced pressure affording a black residue which was used without further purification. MS (ES⁺) m/z 505 (M+H)⁺.

Step 10: methγl (9RΛ lSΛ4S)-\4-tert-butΥl-\3-oxo-S-oxa-\2Λ5- diazatetracvclor20.3.1.1²'⁶.l⁹'¹²loctacosa-l(26).2(28).3.5.22.24-hexaene-l l-carboxylate l04 Pd/C 10% (20% w/w) was added to a 0.025 M solution of methyl (9R,\ l^M^^O^-M-tert-butyl- 13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.1²'⁶.l⁹'¹²]octacosa-l(26),2(28),3,5,20,22,24-heptaene- 11-carboxylate 103 in MeOH containing trifiuoroacetic acid (1.0 eq.). The reaction mixture was stirred under a hydrogen atmosphere for 6h. Solids were filtered off and the resulting solution was evaporated under reduced pressure. The residue was used without further purification in the following step. MS (ES⁺) m/z 507 (M+H)⁺.

Step 11: (9i?.116'.14^-14-tert-butyl-13-oxo-8-oxa-12.15-diazatetracvclor20.3.1.1²'⁶.l⁹'¹²loctacosa- l(26).2(28).3.5.22.24-hexaene-l l-carboxylic acid 105 LiOH (3.0 eq.) was added to a 0.05 M solution of methyl (9R,\ \S,\4S)-14-tert-butyl-\3-oxo-8- oxa-12,15-diazatetracyclo[20.3.1.1²'⁶.l⁹'¹²]octacosa-l(26),2(28),3,5,22,24-hexaene-l l-carboxylate 104 in a mixture of THFiEtOHiH₂O (2: 1:1). The reaction mixture was stirred at 40⁰C for 2 h then the solvent was evaporated under reduced pressure. Aqueous HCl (IN) was added to reach pH = 6 and the mixture was evaporated to dryness to yield a dark solid which was used without further purification. MS (ES⁺) m/z 493 (M+H)⁺.

Step 12: (9RΛ 16'.14^-14-tert-butyl-N-((li?.2^-l-(r(cvclopropylsulfonyl)aminolcarbonyli-2- vinylcvclopropyl)-13-oxo-8-oxa-12J5-diazatetracvclor20.3.1.1²'⁶.l⁹'¹²loctacosa- l(26).2(28).3.5.22.24-hexaene-l 1-carboxamide 142

( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropanaminium chloride 48 (prepared as described in WO 03/099274) (1.2 eq.) and HATU (1.2 eq.) were added to a 0.1M solution of (9R,1 \S,\4S)-14-tert-butyl-\3-oxo-8-oxa-\2,\5- diazatetracyclo[20.3.1.1²'⁶.l⁹'¹²]octacosa-l(26),2(28),3,5,22,24-hexaene-l 1-carboxylic acid 105 in DMF containing DIPEA (4.0 eq.). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness, dissolved in DMSO and purified by RP-HPLC (stationary phase: column Waters XTerra Ci₈, 5um, 19x150. Mobile phase: MeCN/H₂O buffered with 0.1% TFA from 30% to 90 % of MeCN in 14 minutes, run time 18 minutes). Fractions containing the pure compound were combined and freeze dried to afford compound 142 (TFA salt)as an off white solid (30 % over 4 steps). ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 10.65 (s, IH), 8.89 (s, IH), 8.65-8.49 (bs, IH), 8.25-8.11 (bs, IH), 7.62-7.56 (m, 2H), 7.51-7.38 (m, 4H), 7.31 (d, J 7.3, IH), 7.24 (d, J 7.3, IH), 5.69-5.53 (m, IH), 5.24 (d, J 17.2, IH), 5.14 (d, J 11.9, IH), 4.71 (d, J 12.4, IH), 4.61 (d, J 12.4, IH), 4.31 (bt, IH), 4.37 (bs, IH), 4.16 (d, J 8.8, IH), 4.04 (d, J 11.9, IH), 3.79 (dd, J 11.5, 3.9, IH), 3.00-2.91 (m, IH), 2.91-2.81 (m, IH), 2.80-2.68 (m, 2H), 2.22 (q, J 17.5, 8.8, IH), 2.02-1.91 (m, IH), 1.83-1.69 (m, 2H), 1.68-1.56 (m, 2H), 1.41-1.24 (m, 5H), 1.22- 1.02 (m, 13H), 0.91 (t, J 7.3, 4H). MS (ES⁺) m/z 705 (M+H)⁺.

Scheme 17

Compound 146: (9R,llS,14S,20^)-14-cyclohexyl-N-((lR,2S)-l-{[(cyclopropylsulfonyl) aminolcarbonylJ-l-vinylcyclopropylJ-lS-oxo-S-oxa-HjlS- diazatetracyclo[20.3.1.1²'⁶.l^{9 12}]octacosa-l(26),2(28),3,5,20,22,24-heptaene-ll-carboxamide

Step 1: methyl (4i?)-4-r(3'-bromobiphenyl-3-yl)methoxyl-l-{(26^f)-2-r(tert-butoxycarbonyl)aminol- 2-cyclohexylacetvU -L-prolinate 106 (25)-[(tert-butoxycarbonyl)amino](cyclohexyl)acetic acid (1.05 eq.), DIPEA (3.2 eq.) and TBTU (1.1 eq.) were added to a 0.12M solution of methyl (4i?)-4-[(3'-bromobiphenyl-3-yl)methoxy]-L- prolinate hydrochloride 97 in DMF. The reaction mixture was stirred at RT for 2h then it was diluted with EtOAc:H₂O and acidified with aqueous (IN) HCl. The phases were separated and the organic layer was washed sequentially with aqueous (IN) HCl, aqueous (2N) NaOH and brine, dried (Na₂SO₄) and evaporated under reduced pressure to afford the title compound 106 (95 % crude yield) as a pale yellow foam which was used without further purification. ¹H NMR (400 MHz, DMSOd₆, 300 K) δ 7.86 (s, IH), 7.70 (d, J 7.8, IH), 7.66-7.57 (m, 3H), 7.54-7.33 (m, 3H), 6.94 (d, J 8.6, IH), 4.65 (d, J 11.6, IH), 4.58 (d, J 11.6, IH), 4.36 (t, J 8.5, IH), 4.32 (bs, IH), 4.19 (d, J 11.1, IH), 4.11 (t, J 11.1, IH), 3.74-3.66 (m, IH), 3.65 (s, 3H), 2.48-2.35 (m, IH), 2.08- 1.97 (m, IH), 1.83-1.55 (m, 6H), 1.44-1.37 (m, IH), 1.34 (s, 9H), 1.22-1.09 (m, 2H), 1.08-0.93 (m, 2H). MS (ES⁺) m/z 629, 631 (M+H)⁺

Step 2: methyl (4i?)-l-((2y)-2-r(tert-butoxycarbonyl)amino1-2-cvclohexylacetyli-4-r(3'- vinylbiphenyl-3 -vDmethoxyl -L-prolinate 107

Potassium vinyltrifiuoroborate (2.0 eq.), Et₃N (2.0 eq.) and PdCl₂(dppf)-DCM adduct (0.05 eq.) were sequentially added to a 0.12 M solution of methyl (4i?)-4-[(3'-bromobiphenyl-3-yl)methoxy]- l-{(25)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylacetyl} -L-prolinate 106 in EtOH. The reaction mixture was stirred with heating at reflux for 3 h then it was cooled down to RT and diluted with H₂OiEtOAc. The phases were separated and the organic layer was washed with brine, dried (Na₂SO₄) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO₂, PE:EtOAc=8:2) to afford the title compound 107 (72%) as a foam. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 7.75 (s, IH), 7.71-7.61 (m, 2H), 7.59 (d, J 7.3, IH), 7.56- 4.43 (m, 3H), 7.39 (d, J 7.3, IH), 6.94 (d, J 8.6, IH), 6.86 (dd, J 17.7, 10.9, IH), 5.98 (d, J 17.7, IH), 5.36 (d, J 10.9, IH), 4.66 (d, J 11.7, IH), 4.58 (d, J 11.7, IH), 4.36 (t, J 8.6, IH), 4.32 (bs, IH), 4.19 (d, J 10.9, IH), 4.15-4.07 (m, IH), 3.73-3.66 (m, IH), 3.65 (s, 3H), 2.46-2.35 (m, IH), 2.07-1.98 (m, IH), 1.82-1.57 (m, 6H), 1.42-1.36 (m, IH), 1.34 (s, 9H), 1.20-1.12 (m, 2H), 1.07- 0.94 (m, 2H). MS (ES⁺) m/z 577 (M+H)⁺

Step 3: methyl (4i?)-l-r(26^f)-2-amino-2-cvclohexylacetyll-4-r(3'-vinylbiphenyl-3-yl)methoxyl-L- prolinate hydrochloride 108

Methyl (4R)- 1 - {(25)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylacetyl} -4- [(3 '-vinylbiphenyl-3 - yl)methoxy] -L-prolinate 107 was suspended in 4M solution of HCl in dioxane (final cone. 1.3 M) and stirred at RT for 2 h. The solvent was removed under reduced pressure, the residue was taken up with Et₂O and evaporated to dryness to afford the title compound 108 (95% crude yield) as a white foam. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 8.15 (bs, 3H), 7.46 (s, IH), 7.72-7.64 (m, 2H), 7.60 (d, J 7.6, IH), 7.57-7.46 (m, 3H), 7.40 (d, J 7.6, IH), 6.87 (dd, J 17.7, 11.1, IH), 5.98 (d, J 17.7, IH), 5.37 (d, J 11.1, IH), 4.65 (s, 2H), 4.46 (t, J 8.5, IH), 4.36 (bs, IH), 4.25-4.18 (m, IH), 4.10 (d, J 11.4, IH), 3.72-3.65 (m, IH), 3.68 (s, 3H), 2.60-2.55 (m, partially obscured by residual DMSO-d6, IH), 2.11-2.00 (m, IH), 1.89-1.61 (m, 6H), 1.32-1.02 (m, 5H). MS (ES⁺) m/z 477 (M+H)⁺

Step 4 : methyl (4R)- 1 - r(2y)-2-cvclohexyl-2-(hex-5 -en- 1 -ylamino)acetyll -4- [(3 '-vinylbiphenyl-3 - vDmethoxyi -L-prolinate 109 Et₃N (2.0 eq.), hex-5-enal (1.0 eq.) (obtained from hex-5-en-l-ol via a PCC oxidation and sodium triacetoxyborohydride (1.3 eq.) were sequentially added to a 0.07 M solution of methyl (4i?)-l- [(25)-2-amino-2-cyclohexylacetyl] -4- [(3 '-vinylbiphenyl-3 -yl)methoxy] -L-prolinate hydrochloride 108 in DCE. The reaction mixture was stirred at RT for 2 h then it was diluted with DCM, saturated aqueous NaHCO₃ and extracted. The collected organic layers were washed with brine, dried (Na₂SO₄) and evaporated under reduced pressure to yield a residue that was purified by flash chromatography (SiO₂, PE:EtOAc=7:3) to afford the title compound 109 (67%) as a colourless oil. ¹H NMR (400 MHz, DMSO-d₆, 300 K) δ 7.74 (s, IH), 7.70-7.43 (m, 7H), 7.35 (d, J 7.6, IH), 6.86 (dd, J 17.7, 10.9, IH), 5.97 (d, J 17.7, IH), 5.79-5.76 (m, IH), 5.36 (d, J 10.9, IH), 4.99-4.87 (m, 2H), 4.64 (s, 2H), 4.43 (t, J 8.3, IH), 4.32 (bs, IH), 4.00 (d, J 11.4, IH), 3.64 (s, 3H), 3.64-3.57 (m, IH), 3.21-3.13 (m, IH), 2.49-2.34 (m, 2H), 2.33-2.22 (m, IH), 2.06-1.97 (m, IH), 1.97-1.83 (m, 3H), 1.75-1.57 (m, 5H), 1.34-1.06 (m, 9H). MS (ES⁺) m/z 559 (M+H)⁺

Step 5: methyl (9iU l>S'.14,S'.20Eyi4-cvclohexyl-13-oxo-8-oxa-12.15- diazatetracvclor20.3.1.1²'⁶.l⁹'¹²loctacosa-l(26).2(28).3.5.20.22.24-heptaene-l l-carboxylate ll0 To a 0.0 IM solution of methyl (4i?)-l-[(25)-2-cyclohexyl-2-(hex-5-en-l-ylamino)acetyl]-4-[(3'- vinylbiphenyl-3-yl)methoxy] -L-prolinate 109 in DCM was added TFA (1.3 eq.) and Zhan I (0.15 eq.). The reaction mixture was stirred under microwave irradiation for 20 min. at 100⁰C. The solvent was evaporated under reduced pressure and the crude material was used in the following step without further purification. MS (ES⁺) m/z 531 (M+H)⁺

Step 6: (9i?.11^14^20E)-14-cvclohexyl-13-oxo-8-oxa-12.15- diazatetracvclor20.3.1.1²'⁶.l⁹'¹²loctacosa-l(26).2(28).3.5.20.22.24-heptaene-l l-carboxylic acid 111 LiOH (3.0 eq.) was added to a 0.04M solution of methyl {9R,\ lS^S^OE^M-cyclohexyl-D-oxo- 8-oxa-12,15-diazatetracyclo[20.3.1.1²'⁶.l⁹'¹²]octacosa-l(26),2(28),3,5,20,22,24-heptaene-l l- carboxylate 110 in a mixture of THF:EtOH:H₂O (2:1:1) and the reaction mixture was stirred at 40⁰C for 2 h. The solvents were removed under reduced pressure, the residue was suspended in EtOAc/H₂O, aqueous (IN) HCl was added to acidic pH and the phases separated. The collected organic layers were dried (Na₂SO₄) and evaporated under reduced pressure to afford a residue which was used without further purification. MS (ES⁺) m/z 517 (M+H)⁺

Step 7: (9RΛ 16'.146'.20E)-14-cvclohexyl-N-((li?.2^-l-(r(cvclopropylsulfonyl)aminolcarbonyli-2- vinylcvclopropyl)-13-oxo-8-oxa-12J5-diazatetracvclor20.3.1.1²'⁶.l⁹'¹²loctacosa- l(26).2(28).3.5.20.22.24-heptaene-l 1-carboxamide 146 Compound 48 (1.2 eq.) and HATU (1.2 eq.) were added to a 0.12M solution of (9R,\ 15,145,20E)- 14-cyclohexyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.1²'⁶.l⁹'¹²]octacosa- l(26),2(28),3,5,20,22,24-heptaene-l 1-carboxylic acid 111 in DMF containing DIPEA (4.0 eq.). The reaction mixture was stirred at RT overnight then it was concentrated to dryness and the residue was dissolved in DMSO and purified by RP-HPLC (stationary phase: column Waters XBridge 19x150 mm, 5um; mobile phase: MeCN/ H₂O buffered with 0.1% TFA from 50% to 90 % of MeCN in 14 min., run time 18 min.). Fractions containing the pure compound were combined and freeze dried to afford compound 146 (TFA salt) as an off white solid (4.0 % over 3 steps). ¹H NMR (400 MHz, DMSOd₆, 300 K) δ 10.73 (s, IH), 8.83 (s, IH), 8.80-8.68 (m, IH), 8.58-8.42 (m, IH), 7.92 (s, 2H), 7.68 (d, J 7.6, IH), 7.62 (d, J 7.6, IH), 7.51-7.40 (m, 2H), 7.29 (t, J 8.1, 2H), 6.58 (d, J 15.7, IH), 6.49-6.37 (m, IH), 5.68-5.54 (m, IH), 5.27 (d, J 16.9, IH), 5.16 (d, J 11.6, IH), 4.74 (d, J 11.9, IH), 4.60 (d, J 11.9, IH), 4.50-4.33 (m, 3H), 4.19 (d, J 11.1, IH), 3.86 (dd, J 11.1, 3.8, IH), 3.18-2.91 (m, 3H), 2.60-2.46 (m, partially obscured by residual DMSO-d6, IH), 2.43-2.24 (m, 2H), 2.19 (q, J 8.8, IH), 2.09-1.97 (m, IH), 1.92-1.65 (m, 9H), 1.64-1.52 (m, IH), 1.38-1.02 (m, HH). MS (ES⁺) m/z 729 (M+H)⁺.

Scheme 18

Compound 138: (2R,4S,7S,14E)-7-cyclohexyl-N-((lR,2S)-1-{[(cyclopropylsulfonyl) amino]carbonyl}-2-vinylcyclopropyl)-12-methoxy-6-oxo-20-phenyl-3,4,6,7,8,9,10,11,12,13- decahydro-2H- 16,18-etheno-2,5-methanopyrido [3,4-r] [ 1 ,5,8] oxadiazacyclononadecine-4- carboxamide

^iSyCyclohexylfliept-ό-en- l-ylamino)acetic acid 68 (R³ = cΗex) Following the procedure described above for Compound 19 Steps 1-2, treatment of cyclohexylglycine tert-butyl ester hydrochloride with hept-6-enal afforded the title compound 68 (76%) as an oil. MS (ES⁺) m/z 254 (M+Η)⁺.

Ethyl 3-(methylamino)-3-phenylacrylate (112) To a solution of ethyl benzoylacetate and methylamine (2M in THF, 8 eq.) in EtOH (1 M) was added acetic acid (8 eq.). The reaction mixture was heated to reflux and stirred for three days. The reaction mixture was concentrated and partition between DCM and IN HCl. The layers were separated and the organic layer was dried (Na₂SO₄), filtered and concentrated to give the title compound 112 (20%) which was used with no further purification.

Step 1: Ethyl 3-r(4-bromo-3-methoxyphenyl)aminol-3-phenylacrylate 113 To a solution of compound 112 and 4-bromo-3-methoxyaniline (1 eq.) in DCM (0.15 M) was added PPTS (1 eq.). The mixture was heated to reflux and stirred for one day. The mixture was cooled and the solids were removed by filtration and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography (SiO₂, PEiEtOAc with EtOAc from 1 to 15%) to give the title compound 113 (80%). ¹H NMR (CDCl₃) δ (ppm) 10.32 (br s, IH), 7.32 (m, 5H), 7.20 (d, J 8.5, IH), 6.19 (dd, J 8.5, 2.5, IH), 6.11 (d, J 2.5, IH), 5.03 (s, IH), 4.21 (q, J 7.0, 2H), 3.50 (s, 3H), 1.32 (t, J 7.0, 3H).

Step 2: 6-Bromo-7-methoxy-2-phenylquinolin-4(l//)-one 114

Dowtherm A (0.19 M) was heated to reflux (~300°C). A mixture of the product 113 in Dowtherm A (2.5 M) was added to the heated Dowtherm A solution portionwise. The mixture was stirred at reflux for Ih after the addition was complete. The mixture was cooled to RT, filtered, and the solid was washed with hexane to give the title compound 114 (86%). ¹H NMR (DMSO-d6) δ (ppm) 11.69 (s, IH), 8.19 (s, IH), 7.82 (m, 2H), 7.59 (m, 3H), 7.35 (s, IH), 6.33 (s, IH), 3.96 (s, 3H).

1-tert-Butyl 2 -methyl (26^*, 45V4- {r(4-bromophenyl)sulfonyl1oxy}pyrrolidine-l,2-dicarboxylate 115 To a solution of 1 -tert-butyl 2-methyl (25^*,45)-4-hydroxypyrrolidine-l,2-dicarboxylate and DABCO (1.6 eq.) in toluene (0.20 M) at O⁰C was added a solution of brosyl chloride (3.14 g, 12.3 mmol) in toluene (0.41 M) and stirring was continued at RT. EtOAc was added and a white precipitate formed, the reaction mixture was stirred for 20 min and filtered. The filtrate was partitioned between EtOAc and 2.5% aqueous NaHCO₃. The layers were separated and the organic was washed with 5% aqueous potassium bisulfate and brine, dried (Na₂SO₄), filtered and concentrated. The resulting oil was triturated with hexane/ether and the resulting white solid recovered by filtration affording the title compound 115 (67%), which was then used without further purification. MS (ES⁺) m/z 464 and 466 (M+F£)⁺.

Step 3: 1-tert-Butyl 2-methyl (2£,4i0-44(6-bromo-7-methoxy-2-phenylquinolin-4- vDoxylpyrrolidine- 1 ,2-dicarboxylate 116

To a solution of compounds 115 and 114 in N-methylpyrrolidine (0.36 M), cesium carbonate (2 eq.) was added. The reaction mixture was heated to 5O⁰C and stirred for 3h and cooled. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCC>3, water and brine, dried (Na₂SO₄), filtered and concentrated. The residue was purified by column chromatography (SiO₂, PEiEtOAc with EtOAc from 1 to 60%) to give the title compound 116 (99%) as a pale yellow solid. MS (ES⁺) m/z 557 and 559 (M+H)⁺.

Step 4: Methyl (4i0-44(7-methoxy-2-phenyl-6-vinylquinolin-4-yl)oxy1-L-prolinate hydrochloride 117 Tributylvinylstannane (1.15 eq.) and tetrakis(triphenylphosphine) palladium(O) (0.07 eq.) were added to a solution of compound 116 in toluene (0.09 M) and the reaction mixture was heated at 100⁰C. After 2Oh volatiles were removed in vacuo and the residue was purified by column chromatography (SiO₂, PEiEtOAc with EtOAc from 1 to 60%) to give a pale yellow solid, that was taken up in a 4N solution of HCl in dioxane (0.31 M). The reaction mixture was stirred for Ih and the resulting white solid recovered by filtration, washed with EtO Ac/petroleum ether affording the title compound 117 (99%) as a pale yellow solid. MS (ES⁺) m/z 405 (M+H)⁺.

Step 5: (2i?,4>S',76'J4E)-7-cvclohexyl-23-methoxy-4-(methoxycarbonyl)-6-oxo-20-phenyl- 3.4.6.7.8.9.10.1 U2.13-decahvdro-2H-16.18-etheno-2.5-methanopyridor3.4- riri,5,81oxadiazacyclononadecin-8-ium trifluoroacetate 118 (R³=cHex)

Following the procedure described for Compound 19 Step 3, treatment of the compounds 117 and 68 with TBTU and DIPEA afforded methyl (4i?)-l-[(25)-2-cyclohexyl-2-(hept-6-en-l- ylamino)acetyl]-4-[(7-methoxy-2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinate (35%) as an oil. MS (ES⁺) m/z 640 (M+H)⁺. Treatment of this material as described for compound 19 Step 4 afforded the title compound 118 (65%) as a solid.

Step 6: (2i?.4^.7^.14E)-7-cvclohexyl-N-((li?.2^-l-{r(cvclopropylsulfonyl) aminolcarbonvU-2- vinylcvclopropyl)-23-methoxy-6-oxo-20-phenyl-3,4,6,7,8,9, 10,11,12, 13-decahvdro-2H- 16,18- etheno -2,5 -methanop yrido [3 ,4-rl [ 1 ,5 , 81 oxadiazacvclononadecine-4-carboxamide 138 Treatment of the compound 118 as described for Compound 19 Steps 6-7 afforded the title compound 138 (54%, TFA salt) as a white solid. MS (ES⁺) m/z 810 (M+H)⁺.

Compound 139: αR,4SJS)-7-cvclohexyl-N-(αR,2S)-l-{[(cvclopropylsulfonyl)aminol carbonyll-Z-vinylcvclopropyD-ZS-methoxy-ό-oxo-ZO-phenyl-S^^J^^JOJl, 12,13,14,15- dodecahvdro-2H-16,18-etheno-2,5-methanopyrido[3,4-rl [1,5,81 oxadiazacyclononadecine-4- carboxamide

Treatment of compound 118 as described for Compound 19 Steps 5-7 afforded the title compound 139 (38%, TFA salt) as a white solid. MS (ES⁺) m/z 812 (M+Η)⁺.

Compound 140: (2R,4S,7S,15ff)-7-cvclohexyl-N-(qR,2SM-

{[fcvclopropylsulfonyl)aminolcarbonyl}-2-vinylcvclopropyl)-24-methoxy-6-oxo-21-phenyl- 3,4,7,8, 9aoaia2a3a4-decahvdro-2H,6H-17a9-etheno-2,5-methanopyrido[3,4- sl [1,5,81 oxadiazacycloicosine-4-carboxamide

A/-[(ιSV carboxy(cvclohexyl)methvHoct-7-en- 1 -aminium trifluoroacetate (68a) Following the procedure described above for Compound 19 Steps 1-2, treatment of cyclohexylglycine tert-butyl ester hydrochloride with oct-7-enal afforded the title compound 68a (19%) as a white solid. MS (ES⁺) m/z 268 (M+Η)⁺.

Step 5 : (2RAS J S, 15E)-7-cvclohexyl-24-methoxy-4-(methoxycarbonyl)-6-oxo-21 -phenyl-

3.4.7.8.9.10.11.12.13.14-decahvdro-2H.6H-17.19-etheno-2.5-methanopyridor3.4- s^~\ [1, 5, 81oxadiazacycloicosin-8-ium trifluoroacetate 118a (n=2, R³=cHex)

Following the procedure described for Compound 118, treatment of compounds 68a and 117 afforded the title compound 118a (19%) as an oil. MS (ES⁺) m/z 626 (M+H)⁺.

Step 6: (2RAS J S.15£V 7-cvclohexyl-N-(Y 1R.2SD- 1 - ( rfcvclopropylsulfonvDaminolcarbonyli -2- vinylcvclopropyl)-24-methoxy-6-oxo-21 -phenyl-3.4.7.8. 9.10.11.12.13.14-decahydro-2H.6H- 17,19-etheno-2,5-methanopyrido[3,4-sl [ 1 ,5 ,81oxadiazacycloicosine-4-carboxamide 140 Treatment of compound 118a as described for Compound 138 afforded the title compound 140 (43%, TFA salt) as a solid. MS (ES⁺) m/z 824 (M+Η)⁺.

Compound 141: (2R,4S,7S)-7-cvclohexyl-N-(qR,2SM-

{[fcvclopropylsulfonyl)aminolcarbonyl}-2-vinylcvclopropyl)-24-methoxy-6-oxo-21-phenyl- 3,4,7,8,9,10,ll,12,13,14,15,16-dodecahvdro-2H,6H-17,19-etheno-2,5-methanopyrido[3,4- sl [1,5,81 oxa diazacycloicosine-4-carboxamide

Treatment of compound 118a as described for Compound 19 Steps 5-7 afforded the title compound 141 (47%, TFA salt) as a white solid. MS (ES⁺) m/z 826 (M+H)⁺.

Compound 147: (2R,4S,7S,14_JE)-7-cyclohexyl-N-((lR,2S)-l-{[(cyclopropylsulfonyl) amino]carbonyl}-2-vinylcyclopropyl)-23-methoxy-12,12-dimethyl-6-oxo-20-phenyl- 3,4,6,7,8,9,10,ll,12,13-decahydro-2H-16,18-etheno-2,5-methanopyrido[3,4-r] [l,5,8]oxadiaza cyclononadecine-4-carboxamide (26^f)-cvclohexyir(4,4-dimethylhept-6-en-l-yl)aminolacetic acid 68b Following the procedure described above for Compound 19 Steps 1-2, treatment of cyclohexylglycine methyl ester hydrochloride with 4,4-dimethylhept-6-enal afforded the title compound 68b (56%) as a solid. ¹H NMR (CD₃OD) δ (ppm) 5.84 (m, IH), 5.06-4.99 (m, 2H), 3.28 (d, J 4.3, IH), 2.98-2.83 (m, 2H), 1.99 (m, 2H), 1.88-1.65 (m, 8H), 1.36-1.16 (m, 7H), 1.99 (s, 6H). MS (ES⁺) m/z 282 (M+H)⁺.

Step 5 : (2RAS J S, 14£V 7-cvclohexyl-23-methoxy-4-(methoxycarbonyiy 12.12-dimethyl-6-oxo-20-

Ohζ^γl-3AMJ.S,9Λ0Λ lΛ2Λ3-dQcahγdro-2HA6ΛS-Qthζ^o-2,5-methanoOy^ήdo\3A- riri,5,81oxadiazacvclononadecin-8-ium trifluoroacetate 118b and (2i?,46^*,76^*J4Z)-7-cvclohexyl-23- methoxy-4-(methoxycarbonviy 12.12-dimethyl-6-oxo-20-phenyl-3.4.6.7.8.9.10.11.12.13- decahydro-2H- 16,18-etheno-2,5-methanopyridor3,4-rl [ 1 ,5 ,81oxadiazacvclononadecin-8-ium trifluoroacetate 118c

Following the procedure described for compound 118, treatment of compounds 117 and 68b afforded after chromatography compounds 118b (80%) and 118c (2%) as oils. MS (ES⁺) m/z 640

(M+H)⁺.

Step 6: (2RASJS.14£V 7-cvclohexyl-N-(Y 1R.2SD- 1 - ( rfcvclopropylsulfonvDaminolcarbonvU -2- vinylcvclopropyl)-23-methoxy-12, 12-dimethyl-6-oxo-20-phenyl-3,4,6,7,8,9,l 0, 11 , 12, 13- decahvdro-2H- 16,18-etheno-2,5-methanopyridor3,4-rl [ 1 ,5 ,81oxadiaza cyclononadecine-4- carboxamide 147

Treatment of compound 118b following Step 6 for compound 138 afforded the title compound 147 (41%, TFA salt) as a solid. ¹H NMR (DMSO-d6) δ (ppm) 10.78 (br s, IH), 8.93-8.68 (br m, 2H), 8.66 (s, IH), 8.30-8.20 (m, 2H), 8.11 (s, IH), 7.67-7.54 (m, 5H), 7.47 (s, IH), 6.76 (d, J 15.7, IH), 6.33-6.23 (m, IH), 5.76 (br s, IH), 5.56 (dt, J 17.1, 9.5, IH), 5.18 (d, J 17.1, IH), 5.09 (d, J 11.9, IH), 4.63 (d, J 11.9, IH), 4.50-4.40 (m, 2H), 4.00 (s, 3H), 4.01-3.90 (m, IH), 3.23-3.12 (m, IH), 2.90 (m, IH), 2.81-2.68 (m, 2H), 2.26-2.06 (m, 4H), 2.00-1.66 (m, 8H), 1.32-0.95 (m, 12H), 0.93 (s, 3H), 0.91(s, 3H). MS (ES⁺) m/z 838 (M+H)⁺.

Compound 148: (2R,4S,7S)-7-cyclohexyl-N-((lR,2S)-l-{[(cyclopropylsulfonyl)amino] carbonylJ-l-vinylcyclopropylJ-lS-methoxy-HjH-dimethyl-ό-oxo-lO-phenyl- 3,4,6,7,8,9,10,ll,12,13,14,15-dodecahydro-2H-16,18-etheno-2,5-methanopyrido[3,4- r] [1,5,8] oxadiazacyclononadecine-4-carboxamide

Treatment of compound 118c as described for Compound 19 Steps 5-7 afforded the title compound 148 (37%, TFA salt) as a white solid. ¹H NMR (DMSO-d6) δ (ppm) 10.83 (br s, IH), 8.79 (s, IH), 8.65-8.55 (br s, IH), 8.51-8.41 (br s, IH), 8.28-8.20 (m, 2H), 7.83 (s, IH), 7.67-7.54 (m, 5H), 7.47 (s, IH), 5.85 (br s, IH), 5.58 (dt, J 16.7, 9.5, IH), 5.22 (d, J 16.7, IH), 5.12 (d, J 11.6, IH), 4.63 (dd, J 9.2, 8.2, IH), 4.41 (d, J 12.1, IH), 4.38-4.31 (br m, IH), 3.98 (s, 3H), 4.01-3.89 (m, IH), 2.97-2.84 (m, 3H), 2.80-2.73 (m, IH), 2.68-2.57 (m, 2H), 2.35-2.25 (m, IH), 2.14 (q, J 8.7, IH), 2.01-1.90 (m, IH), 1.81-0.99 (m, 22H), 0.85 (s, 3H), 0.77(s, 3H). MS (ES⁺) m/z 840 (M+H)⁺.

Compound 149: (2R,4S,7S,14Z)-7-cyclohexyl-N-((lR,2S)-l-{[(cyclopropylsulfonyl) aminolcarbonylJ-l-vinylcyclopropylJ-lS-methoxy-HjH-dimethyl-ό-oxo-lO-phenyl- 3,4,6,7,8,9,10,11, 12,13-decahydro-2H-16,18-etheno-2,5-methanopyrido[3,4-r] [l,5,8]oxadiaza cyclononadecine-4-carboxamide

Treatment of compound 118c as described for Compound 19 Steps 6-7 afforded the title compound 149 (24%, TFA salt) as a white solid. MS (ES⁺) m/z 838 (M+Η)⁺.

Scheme 19

Compound 143: (2R,4S,7S,14Z)-7-cyclohexyl-N-((lR,2S)-l- {[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-23-methoxy-6-oxo- 3,4,6,7,8,9,10,ll,12,13-decahydro-2H-16,18-(ethanediylidene)-2,5-methanopyrido[3,2- r] [1,5,8] oxadiazacyclononadecine-4-carboxamide

(2iT)-3-(4-Bromo-3-metrioxyphenyl)acrylic acid 119

To a solution of l-bromo-4-iodo-2-methoxybenzene (L. A. Ηasvold et al., US 2004/0254159) in MeCN (1.1 M) was added acrylic acid (1.24 eq.), TEA (2.5 eq.) and palladium acetate (0.03 eq). The reaction mixture was heated to 9O⁰C for 40 min, cooled to RT and poured into IN HCl. After stirring for 30 min, the solid was filtered, heated to reflux in EtOH (2.3 M), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1 : 1 EtOH: hexane to give the desired product 119. LRMS ESI⁺ (M+H)⁺ 257.0.

Step 1: 7-Bromo-6-methoxyisoquinolin-l(2//)-one 120 Compound 119 was azeotroped with benzene, suspended in benzene (0.5 M) with TEA (1.4 eq.), diphenylphosphoryl azide (1 eq.) was added and the reaction mixture stirred at RT for Ih. The mixture was filtered through a pad of silica and eluted with toluene, the volatiles evaporated, the residue resuspended in diphenylmethane (0.5 M) and the mixture heated to reflux for 3h (internal temperature 25O⁰C). The reaction mixture was allowed to cool to RT, stirred overnight, filtered and the solid washed with hexanes to give a tan solid (60%). LRMS ESI⁺ (M+H)⁺ 254.1.

Step 2: 7-Bromo-l-chloro-6-methoxyisoquinoline 121

A mixture of compound 120 in phosphorus oxychloride (0.6 M) was heated to reflux for 2h, cooled to RT, the volatiles evaporated and the residue partitioned between 3N NaOH and DCM. The organic phase was dried (Na₂SO₄), solvent evaporated and the solid triturated with Et₂O and filtered to give a solid (74%). LRMS ESI⁺ (M+H)⁺ 274.0.

Step 3: (4i?)-4-r(7-bromo-6-methoxyisoquinolin-l-yl)oxyl-l-(tert-butoxycarbonyl)-L-proline 122 To a solution of trans 4-hydroxy L-BOC-proline in DMSO (0.23 M) at RT potassium t-butoxide (3 eq.) was added. The reaction mixture was stirred at RT for 30 min, cooled to 15 ⁰C and compound 121 (1 eq) was added as a solution DMSO (0.9 M), the reaction mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was quenched with ice-cold 10% citric acid solution and partitioned with EtOAc. The organic layer was washed with aqueous citric acid solution, water and brine and the aqueous phases back extracted with EtOAc. The combined organic phases were dried (Na₂SO₄) and the solvent evaporated. LRMS ESI⁺ (M+H-tBu)⁺ 411.2.

Step 4: (26^*,4i?)-2-(methoxycarbonyl)-4-r(6-methoxy-7-vinylisoquinolin- 1 -vDoxylpyrrolidinium chloride 123

To a solution of compound 122 in MeOH (0.1 M) was added TMS-diazomethane (4.2 eq.) and the mixture was stirred at RT for 20 min. Volatiles were evaporated and the crude purified by chromatography to obtain \-tert-h\xty\ 2-methyl (25^*,4i?)-4-[(7-bromo-6-methoxyisoquinolin-l- yl)oxy]pyrrolidine-l,2-dicarboxylate as a pale orange foam (79%). To the previous compound dissolved in toluene (0.1 M) tetrakis-(triphenylphospin)-palladium(0) (0.1 eq.) and vinyltri-N- butyltin (1 eq) were added and the mixture was heated at 100⁰C for 2Oh. Volatiles were evaporated and the residue purified by chromatography to obtain \-tert-h\xty\ 2-methyl (25^*,4i?)-4-[(6-methoxy- 7-vinylisoquinolin-l-yl)oxy]pyrrolidine-l,2-dicarboxylate as a pale yellow foam (45%) that was treated with HCl 4N in dioxane (26 eq) at RT. After 30 min volatiles were evaporated to obtain the title compound 123 in quantitative yield. MS (ES⁺) m/z 329 (M+H)⁺. Step 5: (2i?,46'J6'J4E)-7-cvclohexyl-23-methoxy-4-(methoxycarbonyl)-6-oxo- 3.4.6.7.8.9.10.11.12.13-decahydro-2H- 16.18-(ethanediylidene)-2.5-methanopyridor3.2- riπ,5,81oxadiazacvclononadecin-8-ium trifluoroacetate 124a (11% yield) and (2RAS J S, 14Z)-I - cvclohexyl-23-methoxy-4-(methoxycarbonyl)-6-oxo-3,4,6,7,8,9, 10,11,12, 13-decahydro-2H- 16,18- (ethanediylidene)-2, 5-methanopyridor3,2-riπ, 5, δloxadiazacyclononadecin-δ-ium trifluoroacetate 124b

Following the procedure described for compound 19 Step 3, treatment of compound 123 and 68 (R³=cHex) with TBTU and DIPEA afforded methyl (4i?)-l-[(25)-2-cyclohexyl-2-(hept-6-en-l- ylamino)acetyl]-4-[(6-methoxy-7-vinylisoquinolin-l-yl)oxy]-L-prolinate (57%) as a oil. Treatment of this material as described for Compound 19 Step 4 afforded after purification by preparative RP- HPLC (stationary phase: column Waters XBridge C 18, 19x100mm, mobile phase MeCN/water buffered with 0.1% TFA) the two title compounds: 124a (first eluted, 59% yield) and 124b (second eluted, 11% yield). MS (ES⁺) m/z 536 (M+F£)⁺.

Step 6: (2i?.4^.7^.14Z)-7-cvclohexyl-N-((li?.2^-l-{r(cvclopropylsulfonyl) aminolcarbonvU-2- vinylcvclopropyl)-23-methoxy-6-oxo-3,4,6,7,8,9,10,l l, 12,13-decahvdro-2H-16,18- (ethanediylidene)-2,5-methanopyrido r3,2-riri,5,81oxadiazacvclononadecine-4-carboxamide 143 Treatment of compound 124b as described for compound 138 Step 6 afforded the title compound 143 (23%, TFA salt) as a solid. MS (ES⁺) m/z 734 (M+H)⁺.

Compound 144: (2R,4S,7S,14_JE)-7-cyclohexyl-N-((lR,2S)-l-{[(cyclopropylsulfonyl) amino]carbonyl}-2-vinylcyclopropyl)-23-methoxy-6-oxo-3,4,6,7,8,9,10, 11,12,13-decahydro- 2H-16,18-(ethanediylidene)-2,5-methanopyrido [3,2-r] [1,5,8] oxadiazacyclo nonadecine-4- carboxamide Treatment of ((2R,4S,7S, 14E)-7-cyclohexyl-23-methoxy-4-(methoxycarbonyl)-6-oxo- 3,4,6,7,8,9, 10,11,12, 13-decahydro-2H- 16, 18-(ethanediylidene)-2,5-methanopyrido[3,2- r][l,5,8]oxadiazacyclononadecin-8-ium trifluoroacetate as described for Compound 138 Step 6 afforded the title compound 144 (25%, TFA salt) as a solid. MS (ES⁺) m/z 734 (M+Η)⁺.

Compound 145: (2R,4S,7S)-7-cyclohexyl-N-((lR,2S)-l-

{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-23-methoxy-6-oxo- 3,4,6,7,8,9,10,ll,12,13,14,15-dodecahydro-2H-16,18-(ethanediylidene)-2,5-methanopyrido [3,2-r] [1,5,8] oxadiazacyclononadecine-4-carboxamide

Treatment of compound 124a as described for Compound 19 Steps 5-7 afforded the title compound 145 (25%, TFA salt) as a white solid. MS (ES⁺) m/z 736 (M+Η)⁺.

Compound 150: (2R,4S,7S,14_JE)-7-cyclohexyl-N-((lR,2S)-l-{[(cyclopropylsulfonyl) amino]carbonyl}-2-vinylcyclopropyl)-23-methoxy-12,12-dimethyl-6-oxo- S^^^^^^O^l^l^S-decahydro-lH-lό^S-CethanediylideneJ-l^-methanopyridoP,!- r] [1,5,8] oxadiaza cyclononadecine-4-carboxamide

Following the procedures described for compound 143 Steps 5-6, treatment of (2<S,4i?)-2- (methoxycarbonyl)-4-[(6-methoxy-7-vinylisoquinolin- 1 -yl)oxy]pyrrolidinium chloride with compound 68b afforded the title compound 150 (14%, TFA salt) as a white solid. MS (ES⁺) m/z 762 (M+Η)⁺.

Compound 134 : (3S,3aR,6S,8R)-N-((lR,2S)-l-{[(cyclopropylsulfonyl)amino]carbonyl}-2- vinylcyclopropyl)-3-methyl-4,10-dioxo-2,3,3a,4,7,8,12,17,18,19,20,21,22,23-tetradecahydro- lH,6H-5,8:ll,13-dimethanopyrrolo [2,1-j] [4,2,8,ll]benzoxatriazacycloicosine-6-carboxamide

(3S)- 1 -hept-6-en- 1 -yl-3-methyl-L-proline 125

Following the procedure described above for Compound 19 Steps 1-2, treatment of methyl (35)-3- methyl-L-prolinate with hept-6-enal afforded the title compound 125 (80 %) as an oil. ¹H NMR (400 MHz, DMSOd₆, 300 K) δ 5.78 (m, IH), 5.03-4.92 (m, 2H), 3.58-3.48 (m, 2H), 3.19-3.01 (m, 2H), 3.07-2.95 (m, IH), 2.34-2.22 (m, IH), 2.12-2.00 (m, 3H), 1.69-1.55 (m, 3H), 1.41-1.22 (m, 4H), 1.18 (d, J 8.8, 3H).

(3^3a^.6^8i?)-6-{r((li?.2^-l-{r(cvclopropylsulfonyl)aminolcarbonvU-2- vinylcvclopropyDaminoicarbonyli-S-methvM.lO-dioxo^JJa^J.δ.12.17.18.19.20.21.22.23- tetradecahvdro-lH,6H-5,8:l l,13-dimethanopyrrolor2,l-/^'ir4,2,8,l llbenzoxatriazacycloicosin-24- ium trifluoroacetate

Following the procedures described for Compound 19, Steps 3-7, treatment of compound 125 with

(25^*,4i?)-2-(methoxycarbonyl)-4-{[(4-vinyl-l,3-dihydro-2H-isoindol-2- yl)carbonyl]oxy}pyrrolidinium chloride afforded the title compound 134 (24 %, TFA salt) as a solid. MS (ES⁺) m/z 696 (M+H)⁺.

Table 1 lists specific compounds of the present invention including the compounds described in the experimental section. The table provides the structure and name of each compound and the mass of its molecular ion plus 1 (M+ 1) as determined via mass spectrometry (ES-MS). The synthetic scheme employed to prepare the compound is indicated in the last column. Table 1

Claims

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3 or 4; n is 0, 1 or 2;

R¹ is CO₂R⁶, CONR⁶SO₂ R⁶ or CONR⁶SO₂N(R⁶),; R² is H, Ci-₆alkyl, C₂-₆alkenyl or C₃-₈cycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;

R³ is Ci-₆alkyl, (CH₂)o-₃C₃-₈cycloalkyl, (CH₂)₀-₃aryl or (CH₂)₀-₃Het, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃, NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂; R⁴ is hydrogen, halo, hydroxy, Ci_₆alkyl, C₂_₆alkenyl, C₂_₆alkynyl, (CH₂)₀-₃C₃_₈cycloalkyl,

(CH₂)₀-₃aryl or Ci_₆alkoxy, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃ NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂;

R⁵ is hydrogen, halo, hydroxy, Ci-₆alkyl, Ci-₆alkoxy, CN, NO₂, C₃_₈cycloalkyl, N(R⁶)₂, aryl or heteroaryl, optionally substituted by 1 to 8 halo, Ci^alkyl or N(R⁶)₂; each R⁶ is independently hydrogen, Ci-₆alkyl or C₃_₈cycloalkyl;

R^a is hydrogen or Ci^alkyl; or R^a and R³ are joined to form a 5- to 7-membered heterocycle containing 1, 2 or 3 N atoms, which heterocycle is optionally substituted by Ci^alkyl; each W is independently halo, OR⁶, C_1-6alkyl, CN, NO₂, CF₃, OCF₃, OCHF₂, CO₂R⁶, CON(R⁶)₂, COR⁶, NR⁶C(O)R⁶, aryl or heteroaryl; Z is a bond, -CH₂- or C=O; M is C₂-i₂alkylene or C₂-i₂alkenylene, optionally substituted by halo, Ci-₆alkyl, (CH₂)o-₃C₃_₈cycloalkyl or (CH₂)o-₃aryl, and optionally containing O, NR⁶, S, SO or SO₂; and

and ring A is pyridinyl, pyrrolidinyl or pyrimidinyl.

2. A compound as claimed in Claim 1 of formula (Io):

or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, 3 or 4; n is 0, 1 or 2;

R¹ is CO₂R⁶, CONR⁶SO₂ R⁶ or CONR⁶SO₂N(R⁶),;

R² is H, Ci-₆alkyl, C₂-₆alkenyl or Q-scycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo; R³ is Ci_₆alkyl, (CH₂)o-3C_3-8cycloalkyl, (CH₂)₀-₃aryl or (CH₂)₀-₃Het, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃, NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂;

R⁴ is hydrogen, C^aUcyl, C₂_₆alkenyl, C₂_₆alkynyl, (CH₂)₀-₃C₃_₈cycloalkyl, (CH₂)₀-₃aryl or d_₆alkoxy, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, d_₆alkyl, NO₂, CN, CF₃ NR⁶SO₂R⁶, SO₂N(R⁶)₂, NHCO₂R⁶, NHCOR⁶, NHCONHR⁶, CO₂R⁶, C(O)R⁶ or CON(R⁶)₂;

R⁵ is hydrogen, halo, hydroxy, Ci-₆alkyl, Ci-₆alkoxy, CN, NO₂, C₃_₈cycloalkyl, N(R⁶)₂, aryl or heteroaryl, optionally substituted by 1 to 8 halo, Ci^alkyl or N(R⁶)₂; each R⁶ is independently hydrogen, Ci-₆alkyl or C₃_₈cycloalkyl; R^a is hydrogen or Ci^alkyl; or R^a and R³ are joined to form a 5- to 7-membered heterocycle containing 1, 2 or 3 N atoms, which heterocycle is optionally substituted by C_halky!; each W is independently halo, OR⁶, C_1-6alkyl, CN, NO₂, CF₃, OCF₃, OCHF₂, CO₂R⁶, CON(R⁶)₂, COR⁶, NR⁶C(O)R⁶, aryl or heteroaryl; Z is a bond or C=O;

M is C₂_i₂alkylene or C₂_i₂alkenylene, optionally substituted by halo, Ci_6alkyl, (CH₂)o-₃C₃_₈cycloalkyl or (CH₂)₀-₃aryl, and optionally containing O, NR⁶, S, SO or SO₂; and ring A is pyridinyl, pyrrolidinyl or pyrimidinyl.

3. A compound as claimed in Claim 1 or Claim 2 wherein m is 1 or 2.

4. A compound as claimed in any one of Claims 1 to 3 wherein n is O or 1.

5. A compound as claimed in any one of Claims 1 to 4 wherein R¹ is CO₂R⁶, CONR⁶SO²R⁶ or CONR⁶SO₂N(R⁶)₂ where R⁶ is as defined in Claim 1.

6. A compound as claimed in any one of Claims 1 to 5 wherein R² is Ci_6alkyl or C₂_6alkenyl.

7. A compound as claimed in any one of Claims 1 to 6 wherein R³ is C^aUcyl, or (CH₂)₀-₃C₃_ scycloalkyl, optionally substituted by halo, OR⁶ or C^aUcyl, where R⁶ is as defined in Claim 1.

8. A compound as claimed in any one of Claims 1 to 7 wherein R^a is hydrogen or Ci_₂alkyl.

9. A compound as claimed in any one of Claims 1 to 6 wherein R^a and R³ are joined to form a 5- or 6- membered heterocycle containing 1 or 2 N atoms, which heterocycle is optionally substituted by Ci^alkyl.

10. A compound as claimed in any one of Claims 1 to 9 wherein R⁴ is hydrogen, Ci_6alkyl, (CH₂)o-₃C₃_₈cycloalkyl, (CH₂)₀-₃phenyl or Ci-₆alkoxy, optionally substituted by halo, OR⁶, SR⁶, N(R⁶)₂, Ci_₆alkyl, NO₂ or CN, where R⁶ is as defined in Claim 1.

11. A compound as claimed in any one of Claims 1 to 10 wherein R⁵ is hydrogen, halo, hydroxy, Ci-₆alkyl, Ci-₆alkoxy, C₃_₈cycloalkyl, aryl or heteroaryl, optionally substituted by N(R⁶)₂, where R⁶ is as defined in Claim 1.

12. A compound as claimed in any one of Claims 1 to 11 wherein each W is independently halo, OR⁶, d_₆alkyl, CF₃, CO₂R⁶, CON(R⁶)₂, COR⁶ or NR⁶C(O)R⁶, where R⁶ is as defined in Claim 1.

13. A compound as claimed in any one of Claims 1 to 12 wherein M is C2-salkylene or C2- galkenylene, optionally substituted by halo, Ci^alkyl or C₃_₆cycloalkyl, and optionally containing O.

14. A compound as claimed in any one of Claims 2 to 13 wherein ring A is pyridinyl or pyrrolidinyl.

15. A compound as claimed in Claim 1 of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴ and M are as defined in Claim 1.

16. A compound as claimed in Claim 1 of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴ and M are as defined in Claim 1.

17. A compound as claimed in Claim 1 of formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴ and M are defined in Claim 1.

18. A compound as claimed in Claim 1 of formula (Id):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴, R⁵, M and W are defined in Claim 1.

19. A compound as claimed in Claim 1 selected from:

(5RJS, 105^*, 12R or <S)-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclo propyl)-10-isopropyl-3,9-dioxo-12-(trifiuoromethyl)-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide, (2R,4S,7S,9R or S)-N-((1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)- 7-isopropyl-6-oxo-9-(trifiuoromethyl)-3,4,6,7,8,9,10,l 1,12,13, 14,15-dodecahydro-2H-16,18- (ethanediylidene)-2,5-methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide, (5R,7S, 1 OR, 17£)-N-(( IR,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)-

3,9-dioxo-10-(trifluoromethyl)-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8- dimethano-4,2,8,11-benzoxatriaza cycl icosine-7-carboxamide,

(5R,7S, 105, 12R or 5)-N-(( li?,25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclo propyl)-10-isopropyl-3,9-dioxo-12-(trifluoromethyl)-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5i?,75, 1 OS, 12i? or 5)- 10-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-3,9-dioxo-12-(trifluoromethyl)-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5R,7S, 105, 12i? or S)- 10-cyclohexyl-N-(( 1R,2/?)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- ethylcyclopropyl)-3,9-dioxo-12-(trifluoromethyl)-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide

(5R,7S, 105, 12R or 5)- 10-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-3,9-dioxo-12-(trifluoromethyl)-l,6,7,9,10,l l,12,13,14,15,16,17-dodecahydro-

5H-2,21:5,8-dimethano-4,2,8,l l-benzoxatriazacyclononadecine-7-carboxamide,

(2R,4S,7R, 14£)-N-(( li?,25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} ^-vinylcyclopropy^-ό- oxo-7-(trifluoromethyl)-3,4,6,7,8,9, 10,11,12, 13-decahydro-2H- 16, 18-(ethanediylidene)-2,5- methanopyrido [3 ,2-r] [ 1 ,5 , 8] oxadiazacyclononadecine-4-carboxamide,

(2R,4S,7R)-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)-6-oxo-7-

(trifluoromethyl)-3,4,6,7,8,9,10,l 1,12,13, 14,15-dodecahydro-2H-16,18-etheno-2,5- methanopyrido [3 ,2-r] [ 1 ,5 , 8] oxadiazacyclononadecine-4-carboxamide,

(5R,7S, 1 OS, 12R or 5)-N-(( 1R.25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-10-isopropyl-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5R,7S, 105, 12R or 5)-N-(( 1R.25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-10-isopropyl-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5R,7S, 105, 17£)-N-(( li?,25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} ^-vinylcyclopropyl)- 10- methyl-3,9-dioxo-6,7,9,10,l l, 12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l- benzoxatriazacycloicosine-7-carboxamide,

(5R,7S, 105, 17E)-N-((\R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)-

13,13-difluoro-10-isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8- dimethano-4,2,8,11-benzoxatriazacyclo icosine-7-carboxamide,

(5R,7S, 105)-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)- 13,13- difluoro-10-isopropyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18-dodecahydro-lH,5H-

2,22:5, 8-dimethano-4,2, 8,11-benzoxatriaza cycloicosine-7-carboxamide,

(5R,7S, 105, 12R or 5, 17£)-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-10-isopropyl-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16-decahydro- lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5RJS, 105, 12R or S)-N-(X 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclo propyl)-10-isopropyl-3,9-dioxo-12-(pentafluoroethyl)-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriaza cycloicosine-7-carboxamide,

(5RJS, 105, 12R or 5)-N-(( 1R,2/?)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- ethylcyclopropyl)-10-isopropyl-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5i?,75, 10S)-N-((\R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} ^-vinylcyclopropyl)- 10- methyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8-dimethano-

4,2,8, 11 -benzoxatriazacycloicosine-7-carboxamide,

(5RJS, 10S)-N-((\R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)- 10- isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro-lH,5H-2,22:5,8- dimethano-4,2,8, 11 -benzoxatriazacycloicosine-7-carboxamide,

(5RJS, 1 OS, 17E)-N-(( li?,25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)- 10- isopropyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8-dimethano-

4,2,8, 11 -benzoxatriazacycloicosine-7-carboxamide,

(5RJS, 1 OS, 12i? or S)- 10-cyclohexyl-N-(( 1R,25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18-dodecahydro-lH,5H-

2,22:5, 8-dimethano-4,2, 8, 11-benzoxatriaza cycloicosine-7-carboxamide,

(2R,4SJS,9R or S)-N-((\R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)-

7-isopropyl-9-methyl-6-oxo-3,4,6,7,8,9,10,l 1,12,13, 14,15-dodecahydro-2H-16,18-etheno-2,5- methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide,

(2R,4SJS,9S or R)-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinylcyclopropyl)-

7-isopropyl-9-methyl-6-oxo-3,4,6,7,8,9,10,l 1,12,13, 14,15-dodecahydro-2H-16,18-etheno-2,5- methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide,

(5RJS, 1 OS, 12R or 5,7E)- 10-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -

2-vinylcyclopropyl)- 12-methyl-3,9-dioxo-6,7,9, 10,11,12, 13, 14, 15,16-decahydro- 1H,5H-

2,22:5, 8-dimethano-4,2, 8, l l-benzoxatriazacycloicosine-7-carboxamide,

(5RJS, 1 OS, 12i? or 5)- 10-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18-dodecahydro-lH,5H-

2,22:5, 8-dimethano-4,2, 8, 11-benzoxa triazacycloicosine-7-carboxamide,

(5RJS, 105, 12R or 5)- 10-cyclohexyl-N-(( 1 R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-l l,12-dimethyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18-dodecahydro- lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5RJS, 1 OS, 12i? or S, 17E)- 10-cyclopentyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfony^amino] carbonyl} -2-vinylcyclopropyl)- 12-methyl-3,9-dioxo-6, 7, 9, 10,11,12, 13, 14,15, 16-decahydro- lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5RJS, 105, 12R or 5, 17E)- 10-cyclopentyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyijamino] carbonyl}-2-vinylcyclopropyl)-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16-decahydro- lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(5R,7S, 105^*, 12R or S)- 10-cyclopentyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-12-methyl-3,9-dioxo-6,7,9,10,l l,12,13,14,15,16,17,18-dodecahydro-lH,5H-

2,22:5, 8-dimethano-4,2, 8, 11-benzoxatriaza cycloicosine-7-carboxamide,

( \R,2S)- 1 -( { [(5R,7S, 1 OS, 12R or S, 1 IE)- 10-cyclohexyl- 12-methyl-3 ,9-dioxo-

6,7,9,10,11,12,13, 14,15, 16-decahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l- benzoxatriazacycloicosin-7-yl] carbonyl} amino)-2-vinylcyclopropanecarboxylic acid,

{5R,1S, 105^*, 12R or S)-N-((\R,2R)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-ethylcyclo propyl)-12-methyl-10-[(15)-l-methylpropyl]-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18- dodecahydro-lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(2R,4S,7S, 14E)-7-cyclopentyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropy^-ό-oxo-S^^J^^JOJ ^^JS-decahydro^H-lόJδ-etheno^^- methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide,

(2i?,45^*,75)-7-cyclopentyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-6-oxo-3,4,6,7,8,9,10,l 1,12,13, 14,15-dodecahydro-2H-16,18-etheno-2,5- methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide,

(35',3ai?,65',8i?)-N-((li?,25)-l-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-3- methyl-4,10-dioxo-2,3,3a,4,7,8,12,17,18,19,20,21,22,23-tetradecahydro-lH,6H-5,8:l l,13- dimethanopyrrolo[2,l-j][4,2,8,l l]benzoxatriazacycloicosine-6-carboxamide,

(5R,7S, 1 OS)- 10-cyclopentyl-N-(( li?,25)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)- 11 -methyl-3 ,9-dioxo-6,7, 10, 11 , 12, 13 , 15 , 16, 17, 18-decahydro- W,5H,9H-

2,22:5, 8-dimethano-4, 14,2, 8, l l-benzodioxatriazacycloicosine-7-carboxamide,

(5R,7S, 1 OS)- 10-cyclopentyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-13,13-dimethyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro- lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxa triazacycloicosine-7-carboxamide,

(5R,7S, 105)- 10-cyclopentyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-l 1,13, 13-trimethyl-3,9-dioxo-6,7,9,10,l 1,12,13, 14,15, 16,17,18-dodecahydro- lH,5H-2,22:5,8-dimethano-4,2,8,l l-benzoxatriazacycloicosine-7-carboxamide,

(2i?,45',75^<, 14£)-7-cyclohexyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-23-methoxy-6-oxo-20-phenyl-3,4,6,7,8,9, 10,11,12, 13-decahydro-2H- 16,18- etheno-2,5-methanopyrido[3,4-r][l,5,8]oxadiazacyclononadecine-4-carboxamide,

(2R,4S,7S)-7-cγdohexγl-N-((\R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-23-methoxy-6-oxo-20-phenyl-3,4,6,7,8,9,10,l 1,12,13, 14,15-dodecahydro-

2H- 16,18-etheno-2,5-methanopyrido[3,4-r] [ 1 ,5 ,8]oxadiazacyclononadecine-4-carboxamide, (2R,4S,7S, 15£)-7-cyclohexyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-24-methoxy-6-oxo-21 -phenyl-3 ,4,7,8, 9,10,11,12,13,14-decahydro-2H,6H-

17,19-etheno-2,5-methanopyrido[3,4-s] [ 1 ,5 ,8]oxadiazacycloicosine-4-carboxamide,

(2i?,45^*,75)-7-cyclohexyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-24-methoxy-6-oxo-21 -phenyl-3 ,4,7,8,9, 10, 11 , 12, 13 , 14, 15 , 16-dodecahydro-

2H,6H- 17,19-etheno-2,5-methanopyrido[3,4-s] [ 1 ,5 ,8]oxadiazacycloicosine-4-carboxamide,

(9R,US,14S)- 14-tert-butyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.1²'⁶.l⁹'¹²]octacosa- l(26),2(28),3,5,22,24-hexaene-l l-carboxamide,

(2R,4S,7S, 14Z)-7-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-23-methoxy-6-oxo-3,4,6,7,8,9, 10,11,12, 13-decahydro-2H- 16,18-

(ethanediylidene)-2,5-methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide,

(2R,4S,7S, 14£)-7-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-23-methoxy-6-oxo-3,4,6,7,8,9, 10,11,12, 13-decahydro-2H- 16,18-

(ethanediylidene)-2,5-methanopyrido[3,2-r][l,5,8]oxadiazacyclo nonadecine-4-carboxamide,

(2i?,45^*,75)-7-cyclohexyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-23-methoxy-6-oxo-3,4,6,7,8,9,10, 11, 12,13, 14,15-dodecahydro-2H-16,18-

(ethanediylidene)-2,5-methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide,

(9R,US,14S,20E)- 14-cyclohexyl-N-(( 1R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.1²'⁶.l⁹'¹²]octacosa- l(26),2(28),3,5,20,22,24-heptaene-l l-carboxamide,

(2R,4S,7S, 14E)-7-cyclohexyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinyl cyclopropyl)-23-methoxy-12, 12-dimethyl-6-oxo-20-phenyl-3,4,6,7,8,9, 10, 11 , 12, 13-decahydro-

2H- 16,18-etheno-2,5-methanopyrido[3,4-r] [ 1 ,5 ,8]oxadiazacyclononadecine-4-carboxamide,

(2i?,45^*,75)-7-cyclohexyl-N-(( \R,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2- vinylcyclopropyl)-23-methoxy-12, 12-dimethyl-6-oxo-20-phenyl-3,4,6,7,8,9, 10, 11 , 12, 13, 14, 15- dodecahydro-2H- 16,18-etheno-2,5-methanopyrido[3,4-r] [ 1 ,5 ,8]oxadiazacyclononadecine-4- carboxamide,

(2R,4S,7S, 14Z)-7-cyclohexyl-N-(( IR,2S)- 1 - { [(cyclopropylsulfonyl)amino]carbonyl} -2-vinyl cyclopropyl)-23-methoxy-12, 12-dimethyl-6-oxo-20-phenyl-3,4,6,7,8,9,l 0, 11 , 12, 13-decahydro-

2H- 16,18-etheno-2,5-methanopyrido[3,4-r] [ 1 ,5 ,8]oxadiazacyclononadecine-4-carboxamide,

(2R,4S,7S, 14£)-7-cyclohexyl-N-(( IR,2S)- 1 - { [(cyclopropylsulfonyl) amino]carbonyl} -2-vinyl cyclopropyl)-23-methoxy-12,12-dimethyl-6-oxo-3,4,6,7,8,9,10,l l,12,13-decahydro-2H-16,18-

(ethanediylidene)-2,5-methanopyrido[3,2-r][l,5,8]oxadiazacyclononadecine-4-carboxamide, or a pharmaceutically acceptable salt thereof.

20. A compound as claimed in any one of Claims 1 to 19 or a pharmaceutically acceptable salt thereof for use in therapy.

21. A compound as claimed in any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment or prevention of infection by hepatitis C virus in a human or animal.

22. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

23. The pharmaceutical composition as claimed in Claim 22 further comprising one or more other agents for the treatment of viral infections such as an antiviral agent, or an immunomodulatory agent such as α-, β- or γ-interferon.

24. A method of inhibiting hepatitis C virus protease and/or of treating or preventing an illness due to hepatitis C virus, the method involving administering to a human or animal subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition as claimed in Claim 22 or Claim 23 or of a compound as claimed in any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof.